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Introduction
Foodndashdrug interactions can lead to alterations in the pharmacokinetic and pharmacodynamic profile of various drugs that may have clinical implications Food may interact with co-administered drugs in various phases (a) before and during gastrointestinal absorption (b) during distribution (c) during metab-olism and (d) during elimination However food has most effect during absorption and metabolism phases (1) There is considerable evidence to suggest that the absorption of various drugs is influenced by the presence of food in the gastrointestinal tract (2) The effects of food are not always predictable and can have clinically significant consequences Some effects of food on the bioavailability of a drug includes changes in gastric emptying drug chelation changes in the activity of drug metabolizing enzymes changes in splanchnic blood flow and plasma protein binding physical or chemical interaction of the meal with the drug product or drug substance and changes in the
metabolic transformation of the drug by the gastroin-testinal wall or liver (3ndash5)
Clarithromycin is a semi-synthetic macrolide anti-biotic containing a 14-membered lactone ring (6 7) which has a unique principle metabolite (14-hydroxy clarithromycin) that has activity equal to or greater than that of the parent drug (8ndash10) Clarithromycin is active intracellularly and its action is static or bactericidal depending on the concentration and the organism Similar to erythromycin and azithro-mycin clarithromycin demonstrated activity against Mycobacterium avium complex (MAC) (11ndash14) The activity of clarithromycin is enhanced by the forma-tion of its active metabolite 14-hydroxy clarithromy-cin and by its extensive distribution into the tissues Both parent and metabolite has been shown to inhibit the strains of Haemophilus influenzae in an additive and synergistic mode (15 16)
Clarithromycin extended-release tablets are used for the treatment of adults with mild-to- moderate infection caused by susceptible strains of the
Clinical Research and Regulatory Affairs 2009 26(4) 73ndash83
R E S E A R C H A R T I C L E
Comparison of effect of fasting and of five different diets on the bioavailability of single oral dose of clarithromycin 500 mg extended release tablet
Sanjay J Gurule1 Tausif Monif1 Priya Ranjan Prasad Verma 2 and Arshad H Khuroo1
1Ranbaxy Research Laboratories Gurgaon Haryana India and 2Department of Pharmaceutical Sciences Birla Institute of Technology Mesra Ranchi India
AbstractThe objective of this cross-over bioavailability study on clarithromycin was to compare the bioavailability under fasting and five different diets in 18 healthy adult male human volunteers using validated LC-MSMS method A single dose of clarithromycin 500 mg extended release tablet was administered at six occasions after overnight fasting after two vegetarian diets (high fat and low fat) two non-vegetarian diets (high fat and low fat) and low fat vegetarian rice Serial blood samples were collected up to 36 h after dose A statis-tically significant food effect was observed for all diets when compared to fasting treatment
Keywords Clarithromycin LC-MSMS bioavailability
Address for Correspondence Sanjay J Gurule Ranbaxy Research Laboratories Plot No GP-5 Sector 18 HSIDC Old DelhindashGurgaon Road Gurgaon 122 015 Haryana India E-mail sanjayguruleranbaxycom
(Received 20 April 2009 revised 11 July 2009 accepted 29 July 2009)
ISSN 1060-1333 printISSN 1532-2521 online copy 2009 Informa UK LtdDOI 10310910601330903252198 httpwwwinformahealthcarecomcrr
Clinical Research and Regulatory Affairs2009
73
26(4)
83
1060-13331532-2521copy 2009 Informa UK Ltd10310910601330903252198
20 April 200929 July 200911 July 2009
CRR
425393
74 Sanjay J Gurule et al
designated microorganisms in the conditions stated below
Acute maxillary sinusitis due to Haemophilus 1 influenzae Moraxella catarrhalis or Streptococcus pneumonia
Acute bacterial exacerbation of chronic bronchitis 2 due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis or Streptococcus pneumonia and
Community-acquired pneumonia due to 3 Haemophilus influenzae Haemophilus parain-fluenzae Moraxella catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae (17)
The pharmacokinetics and tolerability of clarithro-mycin extended release (ER) have been discussed in several studies Guay et al (18) described the results of three studies of the steady-state pharmacokinetic profiles of clarithromycin and its active metabolite 14-hydroxy clarithromycin after multiple oral doses of clarithromycin 500 mg ER tablets once daily as well as the effect of administration in the fasting and fed regimen They found that the bioavailability (AUC) of the ER tablet was 30 lower when administered under fasting compared with fed conditions
Gaete et al (19) performed the compara-tive bioequivalence study on two formulations of clarithromycin 500-mg modified release tablets on 16 healthy male volunteers The plasma clarithromy-cin concentrations were determined by microbiologic assay The two products were found to be bioequiva-lent according to US Food and Drug Administration (FDA) guidelines
Cheng et al (20) investigated the effect of grapefruit juice on inhibition of clarithromycin metabolism Twelve healthy subjects were given water or grape-fruit juice before and after a clarithromycin dose of 500 mg in a randomized cross-over study They found that administration of grapefruit juice increased the time to peak concentration of both clarithromycin and 14-hydroxy clarithromycin but did not affect other pharmacokinetic parameters In a 26 healthy volunteer study Chu et al (21) investigated that food intake before administration of clarithromycin immediate-release tablets increases the bioavailabil-ity of clarithromycin by ~ 25 They also concluded that this increase was considered to have little or no clinical significance and immediate-release clarithro-mycin could be taken with or without food
Alkhalidi et al (22) evaluated the pharmacoki-netic parameters of clarithromycin extended 500 mg tablet under fasting and fatty meal conditions in
38 Jordanian volunteers The Cmax
and AUC for test and reference formulation in fed condition were found to be increased concluding the effect of food
Clarithromycin extended-release tablets pro-vide lower and later steady-state peak plasma concentrations and equivalent 24-h AUCs for both clarithromycin and its active metabolite 14-hydroxy clarithromycin relative to an equal total daily dose of clarithromycin immediate-release tablets It also provides extended absorption of clarithromycin from the gastrointestinal tract after oral administration Although the extent of formation of 14-hydroxy clari-thromycin after oral administration of clarithromycin extended release tablets (two 500-mg tablets once daily) was not affected by food administration under fasting conditions was associated with an ~ 30 lower clarithromycin AUC relative to administration with food (18) Therefore it is recommended that clarithromycin extended-release tablets should be administered with food (17)
The objective of the present study was to assess the effect of different dietary status on the clari-thromycin extended release 500 mg tablet India is a country largely inhabited by vegetarians and most non-vegetarians cannot afford to consume this diet more than once or twice a week It will there-fore be worthwhile to study the effect of isocaloric vegetarian and non-vegetarian diets (each with low and high fat content) on the oral bioavailability of clarithromycin extended release formulation In this study
Plasma concentrations were determined by rapid 1 and sensitive LC-MSMS method which is highly selective for clarithromycin and its active metabolite 14-hydroxy clarithromycin (23)
Complete validation as per regulatory requirements 2 has been done before initiating the project All parameters met acceptance limits
Study was conducted with GCP and GLP 3 compliance
Almost all types of meals were taken into account to 4 check drugndashfood interaction
Experimental methods
Materials
Clarithromycin and erythromycin were procured from USP 14-hydroxy clarithromycin was supplied from analytical department of Ranbaxy Research Laboratory Gurgaon Methanol and acetonitrile were of HPLC grade purchased from Sigma-Aldrich
Bioavailability of single oral dose of clarithromycin 75
(USA) Ammonium acetate was obtained from Fluka (Buchs Switzerland) Water was purified using Milli-Q device (Millipore Moscheim Cedex France) Drug-free human plasma of healthy volunteers was obtained from Ranbaxy Clinical Pharmacology Unit (Majeedia New Delhi India) To ensure the safety during usage all batches of plasma were screened for Hepatitis B and C HIV (human immunodefi-ciency virus) 1 and 2 malaria and syphilis Human plasma batches free of significant interference were used to prepare calibration standards and quality control samples
Clinical study design
The protocol was reviewed and approved by Jamia Hamdard Institution Review Board (IRB) All vol-unteers were healthy adult males who gave written consent before participating in the study The pro-tocol had pre-defined inclusionexclusion criteria The average (plusmn SD) age and weight of volunteers was 272 plusmn 59 years and 549 plusmn 58 kg respectively (Table 1) Prior to dosing each volunteer had undergone physi-cal examination and laboratory tests of hematologic hepatic and renal functions Only medically healthy
volunteers with clinically normal laboratory profiles were enrolled in the study
The study was designed as an open label bal-anced randomized six-treatment six-period six- sequence single-dose cross-over bioavailability study in 18 healthy adult male human volunteers None of the enrolled volunteers had history of allergy to clarithromycin and other macrolide antibiotics Volunteers did not receive any medication during the study and 2 weeks prior to start of study All the volunteers abstained from xanthine-containing food or beverages or alcohol products for 48 h prior to dosing and during housing in each period as instructed Volunteers were admitted in the clinical pharmacology unit from 12 h before dose and were discharged 24 h after dose during each period After discharge ambulatory sample collection was done at 36 h A clinical nutritionist prepared five differ-ent study diets The order of receiving treatments for each volunteer during the six periods of the study was determined according to SAS generated randomization schedule Each volunteer received one 500 mg clarithromycin extended release tablet (Ranbaxy Laboratories Ltd) with 240 mL of drinking water according to the following treatments on six different days separated by 5 days wash-out period
Treatment A A single oral dose of clarithromycin 500 mg XL tablet under fasting conditions
Treatment B A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat vegetarian diet
Treatment C A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat non-vegetarian diet
Treatment D A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian diet
Treatment E A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat non-vegetarian diet
Treatment F A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian rice diet
High-fat vegetarian diet (B) was composed of whole bullmilk (200 mL) cheese pakora (55 g) one cheese toast cheese (30 g) butter (18 g) green chatni (15 g) and roasted peanuts (20 g)
High-fat non-vegetarian diet (C) was composed of bullchicken (60 g) whole milk (240 mL) hash brown potato 120 (g) two fried eggs two bread slices and butter (8 g)
Table 1 Demographic details of study subjectsParameter Statistics n = 18Age (years) n 18
Mean 272SD 59CV 218Minimum 19Maximum 40
Age category n () 18ndash25 8 (44)26ndash30 5 (28)31ndash35 3 (17)gt 35 2 (11)
Gender n () Male 18 (100)Female 0
Height (cm) n 18Mean 1651SD 50CV 30Minimum 157Maximum 176
Weight (kg) n 18Mean 549SD 58CV 106Minimum 46Maximum 66
SD Standard deviation CV Coefficient of variation
76 Sanjay J Gurule et al
Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)
Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana
Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana
The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis
Tolerability
Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms
Product assays and in vitro dissolution testing
Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations
Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma
The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)
Pharmacokinetic methodology
WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C
max T
max and AUC
The area under the curve to the last measurable con-centration (AUC
0ndasht) was calculated by the linear trap-
ezoidal rule The area under the curve extrapolated to infinity (AUC
0ndashinf) was calculated as AUC
0ndasht + CtK
el
where Ct is the last measurable concentration The elimination rate constant (K
el) was obtained as the
slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase
Terminal half life (t12
) was calculated as 0693Kel
The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated
Statistical analysis
Statistical analysis was performed on log trans-formed pharmacokinetic parameter C
max and AUC
The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C
max AUC
0ndasht and AUC
0ndashinf SAS ver-
sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C
max AUC
0ndasht and AUC
0ndashinfin
Results
There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from
Bioavailability of single oral dose of clarithromycin 77
different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study
One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria
Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose
of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments
Tolerability
Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results
Product assays and in vitro dissolution testing
As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004
Effect of food on the bioavailability of clarithromycin
Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T
max C
max AUC
0ndasht AUC
0ndashinf K
el T
12 mean residence
time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T
max of clarithromycin in the fasting
state was 853 plusmn 471 h Tmax
observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T
max of
14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T
max was 773 plusmn 228 h for high-fat
vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T
max for
high-fat non-vegetarian diet remained the same as fasting state
An increase in Cmax
was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C
max was observed with the high-fat vegetarian diet
for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet
AUC0ndasht
also increased like Cmax
with all diets for clarithromycin and 14-hydroxy clarithromycin and
200018001600140012001000800600400200
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean ClarithromycinConcentration Versus Time
Cla
rithr
omyc
in M
ean
Con
cent
ratio
n in
Pla
sma
(ng
mL) A A Error
B B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
700
600
500
400
300
200
100
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time
14-H
ydro
xy C
larit
hrom
ycin
Mea
nC
once
ntra
tion
in P
lasm
a (n
gm
L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
78 Sanjay J Gurule et al
Tabl
e 3
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on a
nd
cea
ran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
14-h
ydro
xy c
lari
thro
myc
in
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
700
plusmn 3
25
773
plusmn 2
28
700
plusmn 2
30
813
plusmn 1
92
773
plusmn 1
98
720
plusmn 3
91
Cm
ax (
ng
mL)
421
09 plusmn
127
28
645
43 plusmn
178
65
641
22 plusmn
161
72
629
33 plusmn
119
48
625
24 plusmn
129
90
447
50 plusmn
162
76
AU
C0ndash
t (h
ng
mL)
911
705
plusmn 3
808
76
106
042
1 plusmn
26
870
710
661
42
plusmn 2
998
38
106
615
6 plusmn
27
212
210
640
11
plusmn 1
761
24
861
740
plusmn 3
038
23
AU
C0ndash
inf (
hn
gm
L)11
607
83
plusmn 5
113
51
118
320
6 plusmn
27
999
812
074
86
plusmn 3
699
03
119
605
2 plusmn
30
477
811
834
27
plusmn 2
015
23
985
924
plusmn 3
657
20
Kel
(h
minus1 )
006
plusmn 0
03
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
007
plusmn 0
02
T1
2 (h
)13
07
plusmn 6
37
900
plusmn 2
59
984
plusmn 3
08
968
plusmn 2
71
948
plusmn 1
85
105
1 plusmn
31
8
Mea
n r
esid
ence
tim
e (h
)22
66
plusmn 9
25
179
0 plusmn
34
019
01
plusmn 3
49
189
9 plusmn
33
118
77
plusmn 1
92
194
7 plusmn
42
8A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
927
76 plusmn
495
75
578
86 plusmn
224
59
607
96 plusmn
179
73
602
64 plusmn
170
89
591
56 plusmn
144
81
851
77 plusmn
374
52
Cle
aran
ce (
Lh
)55
56
plusmn 3
353
447
7 plusmn
11
9744
59
plusmn 1
211
445
4 plusmn
12
6443
60
plusmn 9
06
570
8 plusmn
19
30
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Tabl
e 2
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on
and
cle
aran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
clar
ith
rom
ycin
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
853
plusmn 4
71
647
plusmn 2
92
626
plusmn 1
79
720
plusmn 2
11
626
plusmn 1
03
633
plusmn 3
24
Cm
ax
(ng
mL)
983
73 plusmn
387
90
195
865
plusmn 8
087
21
888
23 plusmn
546
12
179
771
plusmn 6
826
11
903
31 plusmn
982
40
132
773
plusmn 4
569
5
AU
C0ndash
t (h
ng
mL)
178
793
2 plusmn
10
264
7021
322
46
plusmn 7
593
70
218
438
8 plusmn
68
812
422
037
82
plusmn 9
446
55
218
821
7 plusmn
68
163
618
359
83
plusmn 5
443
58
AU
C0ndash
inf (
hn
gm
L)20
371
17
plusmn 1
121
407
225
678
9 plusmn
77
260
623
011
87
plusmn 6
538
90
232
521
5 plusmn
95
058
323
125
29
plusmn 6
508
92
196
247
7 plusmn
52
760
2
Kel
(h
minus1 )
010
plusmn 0
04
012
plusmn 0
02
011
plusmn 0
02
012
plusmn 0
04
011
plusmn 0
02
010
plusmn 0
03
T1
2 (h
)7
87 plusmn
37
75
96 plusmn
08
86
61 plusmn
13
96
38 plusmn
15
46
45 plusmn
13
07
14 plusmn
19
4
Mea
n re
sid
ence
tim
e (h
)15
83
plusmn 5
27
131
5 plusmn
21
914
10
plusmn 1
48
142
1 plusmn
17
514
15
plusmn 1
53
146
6 plusmn
22
5A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
387
35 plusmn
324
40
210
11 plusmn
74
1722
945
plusmn 1
013
722
180
plusmn 8
876
224
16 plusmn
97
8728
661
plusmn 1
291
2
Cle
aran
ce (
Lh
)37
15
plusmn 3
058
245
6 plusmn
79
123
61
plusmn 7
29
243
1 plusmn
79
523
46
plusmn 7
30
272
4 plusmn
74
3
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Bioavailability of single oral dose of clarithromycin 79
maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)
There was no significant difference in values of AUC
0ndashinf when diets were compared with fasting for
clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin
Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C
max
AUC0ndasht
and AUC0ndashinf
are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively
A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin
Effect of fat (low vs high) on the bioavailability of clarithromycin
Cmax
AUC and Tmax
remain the same between high-fat vegetarian and non-vegetarian diets for
clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K
el also
Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin
There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T
max K
el and half-life was
observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin
Statistical evaluation (treatment effect using least square means)
Significant effect was observed for Cmax
AUC0ndasht
and AUC
0ndashinf and C
max AUC
0ndasht when fasting was compared
against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C
max p-value less
than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C
max for clarithromycin and
Cmax
AUC0ndasht
and AUC0ndashinf
for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect
Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for 14-hydroxy clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804
Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
74 Sanjay J Gurule et al
designated microorganisms in the conditions stated below
Acute maxillary sinusitis due to Haemophilus 1 influenzae Moraxella catarrhalis or Streptococcus pneumonia
Acute bacterial exacerbation of chronic bronchitis 2 due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis or Streptococcus pneumonia and
Community-acquired pneumonia due to 3 Haemophilus influenzae Haemophilus parain-fluenzae Moraxella catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae (17)
The pharmacokinetics and tolerability of clarithro-mycin extended release (ER) have been discussed in several studies Guay et al (18) described the results of three studies of the steady-state pharmacokinetic profiles of clarithromycin and its active metabolite 14-hydroxy clarithromycin after multiple oral doses of clarithromycin 500 mg ER tablets once daily as well as the effect of administration in the fasting and fed regimen They found that the bioavailability (AUC) of the ER tablet was 30 lower when administered under fasting compared with fed conditions
Gaete et al (19) performed the compara-tive bioequivalence study on two formulations of clarithromycin 500-mg modified release tablets on 16 healthy male volunteers The plasma clarithromy-cin concentrations were determined by microbiologic assay The two products were found to be bioequiva-lent according to US Food and Drug Administration (FDA) guidelines
Cheng et al (20) investigated the effect of grapefruit juice on inhibition of clarithromycin metabolism Twelve healthy subjects were given water or grape-fruit juice before and after a clarithromycin dose of 500 mg in a randomized cross-over study They found that administration of grapefruit juice increased the time to peak concentration of both clarithromycin and 14-hydroxy clarithromycin but did not affect other pharmacokinetic parameters In a 26 healthy volunteer study Chu et al (21) investigated that food intake before administration of clarithromycin immediate-release tablets increases the bioavailabil-ity of clarithromycin by ~ 25 They also concluded that this increase was considered to have little or no clinical significance and immediate-release clarithro-mycin could be taken with or without food
Alkhalidi et al (22) evaluated the pharmacoki-netic parameters of clarithromycin extended 500 mg tablet under fasting and fatty meal conditions in
38 Jordanian volunteers The Cmax
and AUC for test and reference formulation in fed condition were found to be increased concluding the effect of food
Clarithromycin extended-release tablets pro-vide lower and later steady-state peak plasma concentrations and equivalent 24-h AUCs for both clarithromycin and its active metabolite 14-hydroxy clarithromycin relative to an equal total daily dose of clarithromycin immediate-release tablets It also provides extended absorption of clarithromycin from the gastrointestinal tract after oral administration Although the extent of formation of 14-hydroxy clari-thromycin after oral administration of clarithromycin extended release tablets (two 500-mg tablets once daily) was not affected by food administration under fasting conditions was associated with an ~ 30 lower clarithromycin AUC relative to administration with food (18) Therefore it is recommended that clarithromycin extended-release tablets should be administered with food (17)
The objective of the present study was to assess the effect of different dietary status on the clari-thromycin extended release 500 mg tablet India is a country largely inhabited by vegetarians and most non-vegetarians cannot afford to consume this diet more than once or twice a week It will there-fore be worthwhile to study the effect of isocaloric vegetarian and non-vegetarian diets (each with low and high fat content) on the oral bioavailability of clarithromycin extended release formulation In this study
Plasma concentrations were determined by rapid 1 and sensitive LC-MSMS method which is highly selective for clarithromycin and its active metabolite 14-hydroxy clarithromycin (23)
Complete validation as per regulatory requirements 2 has been done before initiating the project All parameters met acceptance limits
Study was conducted with GCP and GLP 3 compliance
Almost all types of meals were taken into account to 4 check drugndashfood interaction
Experimental methods
Materials
Clarithromycin and erythromycin were procured from USP 14-hydroxy clarithromycin was supplied from analytical department of Ranbaxy Research Laboratory Gurgaon Methanol and acetonitrile were of HPLC grade purchased from Sigma-Aldrich
Bioavailability of single oral dose of clarithromycin 75
(USA) Ammonium acetate was obtained from Fluka (Buchs Switzerland) Water was purified using Milli-Q device (Millipore Moscheim Cedex France) Drug-free human plasma of healthy volunteers was obtained from Ranbaxy Clinical Pharmacology Unit (Majeedia New Delhi India) To ensure the safety during usage all batches of plasma were screened for Hepatitis B and C HIV (human immunodefi-ciency virus) 1 and 2 malaria and syphilis Human plasma batches free of significant interference were used to prepare calibration standards and quality control samples
Clinical study design
The protocol was reviewed and approved by Jamia Hamdard Institution Review Board (IRB) All vol-unteers were healthy adult males who gave written consent before participating in the study The pro-tocol had pre-defined inclusionexclusion criteria The average (plusmn SD) age and weight of volunteers was 272 plusmn 59 years and 549 plusmn 58 kg respectively (Table 1) Prior to dosing each volunteer had undergone physi-cal examination and laboratory tests of hematologic hepatic and renal functions Only medically healthy
volunteers with clinically normal laboratory profiles were enrolled in the study
The study was designed as an open label bal-anced randomized six-treatment six-period six- sequence single-dose cross-over bioavailability study in 18 healthy adult male human volunteers None of the enrolled volunteers had history of allergy to clarithromycin and other macrolide antibiotics Volunteers did not receive any medication during the study and 2 weeks prior to start of study All the volunteers abstained from xanthine-containing food or beverages or alcohol products for 48 h prior to dosing and during housing in each period as instructed Volunteers were admitted in the clinical pharmacology unit from 12 h before dose and were discharged 24 h after dose during each period After discharge ambulatory sample collection was done at 36 h A clinical nutritionist prepared five differ-ent study diets The order of receiving treatments for each volunteer during the six periods of the study was determined according to SAS generated randomization schedule Each volunteer received one 500 mg clarithromycin extended release tablet (Ranbaxy Laboratories Ltd) with 240 mL of drinking water according to the following treatments on six different days separated by 5 days wash-out period
Treatment A A single oral dose of clarithromycin 500 mg XL tablet under fasting conditions
Treatment B A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat vegetarian diet
Treatment C A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat non-vegetarian diet
Treatment D A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian diet
Treatment E A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat non-vegetarian diet
Treatment F A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian rice diet
High-fat vegetarian diet (B) was composed of whole bullmilk (200 mL) cheese pakora (55 g) one cheese toast cheese (30 g) butter (18 g) green chatni (15 g) and roasted peanuts (20 g)
High-fat non-vegetarian diet (C) was composed of bullchicken (60 g) whole milk (240 mL) hash brown potato 120 (g) two fried eggs two bread slices and butter (8 g)
Table 1 Demographic details of study subjectsParameter Statistics n = 18Age (years) n 18
Mean 272SD 59CV 218Minimum 19Maximum 40
Age category n () 18ndash25 8 (44)26ndash30 5 (28)31ndash35 3 (17)gt 35 2 (11)
Gender n () Male 18 (100)Female 0
Height (cm) n 18Mean 1651SD 50CV 30Minimum 157Maximum 176
Weight (kg) n 18Mean 549SD 58CV 106Minimum 46Maximum 66
SD Standard deviation CV Coefficient of variation
76 Sanjay J Gurule et al
Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)
Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana
Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana
The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis
Tolerability
Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms
Product assays and in vitro dissolution testing
Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations
Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma
The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)
Pharmacokinetic methodology
WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C
max T
max and AUC
The area under the curve to the last measurable con-centration (AUC
0ndasht) was calculated by the linear trap-
ezoidal rule The area under the curve extrapolated to infinity (AUC
0ndashinf) was calculated as AUC
0ndasht + CtK
el
where Ct is the last measurable concentration The elimination rate constant (K
el) was obtained as the
slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase
Terminal half life (t12
) was calculated as 0693Kel
The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated
Statistical analysis
Statistical analysis was performed on log trans-formed pharmacokinetic parameter C
max and AUC
The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C
max AUC
0ndasht and AUC
0ndashinf SAS ver-
sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C
max AUC
0ndasht and AUC
0ndashinfin
Results
There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from
Bioavailability of single oral dose of clarithromycin 77
different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study
One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria
Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose
of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments
Tolerability
Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results
Product assays and in vitro dissolution testing
As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004
Effect of food on the bioavailability of clarithromycin
Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T
max C
max AUC
0ndasht AUC
0ndashinf K
el T
12 mean residence
time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T
max of clarithromycin in the fasting
state was 853 plusmn 471 h Tmax
observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T
max of
14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T
max was 773 plusmn 228 h for high-fat
vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T
max for
high-fat non-vegetarian diet remained the same as fasting state
An increase in Cmax
was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C
max was observed with the high-fat vegetarian diet
for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet
AUC0ndasht
also increased like Cmax
with all diets for clarithromycin and 14-hydroxy clarithromycin and
200018001600140012001000800600400200
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean ClarithromycinConcentration Versus Time
Cla
rithr
omyc
in M
ean
Con
cent
ratio
n in
Pla
sma
(ng
mL) A A Error
B B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
700
600
500
400
300
200
100
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time
14-H
ydro
xy C
larit
hrom
ycin
Mea
nC
once
ntra
tion
in P
lasm
a (n
gm
L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
78 Sanjay J Gurule et al
Tabl
e 3
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on a
nd
cea
ran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
14-h
ydro
xy c
lari
thro
myc
in
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
700
plusmn 3
25
773
plusmn 2
28
700
plusmn 2
30
813
plusmn 1
92
773
plusmn 1
98
720
plusmn 3
91
Cm
ax (
ng
mL)
421
09 plusmn
127
28
645
43 plusmn
178
65
641
22 plusmn
161
72
629
33 plusmn
119
48
625
24 plusmn
129
90
447
50 plusmn
162
76
AU
C0ndash
t (h
ng
mL)
911
705
plusmn 3
808
76
106
042
1 plusmn
26
870
710
661
42
plusmn 2
998
38
106
615
6 plusmn
27
212
210
640
11
plusmn 1
761
24
861
740
plusmn 3
038
23
AU
C0ndash
inf (
hn
gm
L)11
607
83
plusmn 5
113
51
118
320
6 plusmn
27
999
812
074
86
plusmn 3
699
03
119
605
2 plusmn
30
477
811
834
27
plusmn 2
015
23
985
924
plusmn 3
657
20
Kel
(h
minus1 )
006
plusmn 0
03
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
007
plusmn 0
02
T1
2 (h
)13
07
plusmn 6
37
900
plusmn 2
59
984
plusmn 3
08
968
plusmn 2
71
948
plusmn 1
85
105
1 plusmn
31
8
Mea
n r
esid
ence
tim
e (h
)22
66
plusmn 9
25
179
0 plusmn
34
019
01
plusmn 3
49
189
9 plusmn
33
118
77
plusmn 1
92
194
7 plusmn
42
8A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
927
76 plusmn
495
75
578
86 plusmn
224
59
607
96 plusmn
179
73
602
64 plusmn
170
89
591
56 plusmn
144
81
851
77 plusmn
374
52
Cle
aran
ce (
Lh
)55
56
plusmn 3
353
447
7 plusmn
11
9744
59
plusmn 1
211
445
4 plusmn
12
6443
60
plusmn 9
06
570
8 plusmn
19
30
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Tabl
e 2
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on
and
cle
aran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
clar
ith
rom
ycin
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
853
plusmn 4
71
647
plusmn 2
92
626
plusmn 1
79
720
plusmn 2
11
626
plusmn 1
03
633
plusmn 3
24
Cm
ax
(ng
mL)
983
73 plusmn
387
90
195
865
plusmn 8
087
21
888
23 plusmn
546
12
179
771
plusmn 6
826
11
903
31 plusmn
982
40
132
773
plusmn 4
569
5
AU
C0ndash
t (h
ng
mL)
178
793
2 plusmn
10
264
7021
322
46
plusmn 7
593
70
218
438
8 plusmn
68
812
422
037
82
plusmn 9
446
55
218
821
7 plusmn
68
163
618
359
83
plusmn 5
443
58
AU
C0ndash
inf (
hn
gm
L)20
371
17
plusmn 1
121
407
225
678
9 plusmn
77
260
623
011
87
plusmn 6
538
90
232
521
5 plusmn
95
058
323
125
29
plusmn 6
508
92
196
247
7 plusmn
52
760
2
Kel
(h
minus1 )
010
plusmn 0
04
012
plusmn 0
02
011
plusmn 0
02
012
plusmn 0
04
011
plusmn 0
02
010
plusmn 0
03
T1
2 (h
)7
87 plusmn
37
75
96 plusmn
08
86
61 plusmn
13
96
38 plusmn
15
46
45 plusmn
13
07
14 plusmn
19
4
Mea
n re
sid
ence
tim
e (h
)15
83
plusmn 5
27
131
5 plusmn
21
914
10
plusmn 1
48
142
1 plusmn
17
514
15
plusmn 1
53
146
6 plusmn
22
5A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
387
35 plusmn
324
40
210
11 plusmn
74
1722
945
plusmn 1
013
722
180
plusmn 8
876
224
16 plusmn
97
8728
661
plusmn 1
291
2
Cle
aran
ce (
Lh
)37
15
plusmn 3
058
245
6 plusmn
79
123
61
plusmn 7
29
243
1 plusmn
79
523
46
plusmn 7
30
272
4 plusmn
74
3
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Bioavailability of single oral dose of clarithromycin 79
maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)
There was no significant difference in values of AUC
0ndashinf when diets were compared with fasting for
clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin
Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C
max
AUC0ndasht
and AUC0ndashinf
are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively
A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin
Effect of fat (low vs high) on the bioavailability of clarithromycin
Cmax
AUC and Tmax
remain the same between high-fat vegetarian and non-vegetarian diets for
clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K
el also
Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin
There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T
max K
el and half-life was
observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin
Statistical evaluation (treatment effect using least square means)
Significant effect was observed for Cmax
AUC0ndasht
and AUC
0ndashinf and C
max AUC
0ndasht when fasting was compared
against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C
max p-value less
than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C
max for clarithromycin and
Cmax
AUC0ndasht
and AUC0ndashinf
for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect
Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for 14-hydroxy clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804
Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
Bioavailability of single oral dose of clarithromycin 75
(USA) Ammonium acetate was obtained from Fluka (Buchs Switzerland) Water was purified using Milli-Q device (Millipore Moscheim Cedex France) Drug-free human plasma of healthy volunteers was obtained from Ranbaxy Clinical Pharmacology Unit (Majeedia New Delhi India) To ensure the safety during usage all batches of plasma were screened for Hepatitis B and C HIV (human immunodefi-ciency virus) 1 and 2 malaria and syphilis Human plasma batches free of significant interference were used to prepare calibration standards and quality control samples
Clinical study design
The protocol was reviewed and approved by Jamia Hamdard Institution Review Board (IRB) All vol-unteers were healthy adult males who gave written consent before participating in the study The pro-tocol had pre-defined inclusionexclusion criteria The average (plusmn SD) age and weight of volunteers was 272 plusmn 59 years and 549 plusmn 58 kg respectively (Table 1) Prior to dosing each volunteer had undergone physi-cal examination and laboratory tests of hematologic hepatic and renal functions Only medically healthy
volunteers with clinically normal laboratory profiles were enrolled in the study
The study was designed as an open label bal-anced randomized six-treatment six-period six- sequence single-dose cross-over bioavailability study in 18 healthy adult male human volunteers None of the enrolled volunteers had history of allergy to clarithromycin and other macrolide antibiotics Volunteers did not receive any medication during the study and 2 weeks prior to start of study All the volunteers abstained from xanthine-containing food or beverages or alcohol products for 48 h prior to dosing and during housing in each period as instructed Volunteers were admitted in the clinical pharmacology unit from 12 h before dose and were discharged 24 h after dose during each period After discharge ambulatory sample collection was done at 36 h A clinical nutritionist prepared five differ-ent study diets The order of receiving treatments for each volunteer during the six periods of the study was determined according to SAS generated randomization schedule Each volunteer received one 500 mg clarithromycin extended release tablet (Ranbaxy Laboratories Ltd) with 240 mL of drinking water according to the following treatments on six different days separated by 5 days wash-out period
Treatment A A single oral dose of clarithromycin 500 mg XL tablet under fasting conditions
Treatment B A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat vegetarian diet
Treatment C A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat non-vegetarian diet
Treatment D A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian diet
Treatment E A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat non-vegetarian diet
Treatment F A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian rice diet
High-fat vegetarian diet (B) was composed of whole bullmilk (200 mL) cheese pakora (55 g) one cheese toast cheese (30 g) butter (18 g) green chatni (15 g) and roasted peanuts (20 g)
High-fat non-vegetarian diet (C) was composed of bullchicken (60 g) whole milk (240 mL) hash brown potato 120 (g) two fried eggs two bread slices and butter (8 g)
Table 1 Demographic details of study subjectsParameter Statistics n = 18Age (years) n 18
Mean 272SD 59CV 218Minimum 19Maximum 40
Age category n () 18ndash25 8 (44)26ndash30 5 (28)31ndash35 3 (17)gt 35 2 (11)
Gender n () Male 18 (100)Female 0
Height (cm) n 18Mean 1651SD 50CV 30Minimum 157Maximum 176
Weight (kg) n 18Mean 549SD 58CV 106Minimum 46Maximum 66
SD Standard deviation CV Coefficient of variation
76 Sanjay J Gurule et al
Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)
Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana
Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana
The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis
Tolerability
Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms
Product assays and in vitro dissolution testing
Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations
Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma
The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)
Pharmacokinetic methodology
WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C
max T
max and AUC
The area under the curve to the last measurable con-centration (AUC
0ndasht) was calculated by the linear trap-
ezoidal rule The area under the curve extrapolated to infinity (AUC
0ndashinf) was calculated as AUC
0ndasht + CtK
el
where Ct is the last measurable concentration The elimination rate constant (K
el) was obtained as the
slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase
Terminal half life (t12
) was calculated as 0693Kel
The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated
Statistical analysis
Statistical analysis was performed on log trans-formed pharmacokinetic parameter C
max and AUC
The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C
max AUC
0ndasht and AUC
0ndashinf SAS ver-
sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C
max AUC
0ndasht and AUC
0ndashinfin
Results
There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from
Bioavailability of single oral dose of clarithromycin 77
different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study
One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria
Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose
of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments
Tolerability
Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results
Product assays and in vitro dissolution testing
As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004
Effect of food on the bioavailability of clarithromycin
Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T
max C
max AUC
0ndasht AUC
0ndashinf K
el T
12 mean residence
time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T
max of clarithromycin in the fasting
state was 853 plusmn 471 h Tmax
observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T
max of
14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T
max was 773 plusmn 228 h for high-fat
vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T
max for
high-fat non-vegetarian diet remained the same as fasting state
An increase in Cmax
was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C
max was observed with the high-fat vegetarian diet
for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet
AUC0ndasht
also increased like Cmax
with all diets for clarithromycin and 14-hydroxy clarithromycin and
200018001600140012001000800600400200
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean ClarithromycinConcentration Versus Time
Cla
rithr
omyc
in M
ean
Con
cent
ratio
n in
Pla
sma
(ng
mL) A A Error
B B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
700
600
500
400
300
200
100
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time
14-H
ydro
xy C
larit
hrom
ycin
Mea
nC
once
ntra
tion
in P
lasm
a (n
gm
L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
78 Sanjay J Gurule et al
Tabl
e 3
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on a
nd
cea
ran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
14-h
ydro
xy c
lari
thro
myc
in
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
700
plusmn 3
25
773
plusmn 2
28
700
plusmn 2
30
813
plusmn 1
92
773
plusmn 1
98
720
plusmn 3
91
Cm
ax (
ng
mL)
421
09 plusmn
127
28
645
43 plusmn
178
65
641
22 plusmn
161
72
629
33 plusmn
119
48
625
24 plusmn
129
90
447
50 plusmn
162
76
AU
C0ndash
t (h
ng
mL)
911
705
plusmn 3
808
76
106
042
1 plusmn
26
870
710
661
42
plusmn 2
998
38
106
615
6 plusmn
27
212
210
640
11
plusmn 1
761
24
861
740
plusmn 3
038
23
AU
C0ndash
inf (
hn
gm
L)11
607
83
plusmn 5
113
51
118
320
6 plusmn
27
999
812
074
86
plusmn 3
699
03
119
605
2 plusmn
30
477
811
834
27
plusmn 2
015
23
985
924
plusmn 3
657
20
Kel
(h
minus1 )
006
plusmn 0
03
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
007
plusmn 0
02
T1
2 (h
)13
07
plusmn 6
37
900
plusmn 2
59
984
plusmn 3
08
968
plusmn 2
71
948
plusmn 1
85
105
1 plusmn
31
8
Mea
n r
esid
ence
tim
e (h
)22
66
plusmn 9
25
179
0 plusmn
34
019
01
plusmn 3
49
189
9 plusmn
33
118
77
plusmn 1
92
194
7 plusmn
42
8A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
927
76 plusmn
495
75
578
86 plusmn
224
59
607
96 plusmn
179
73
602
64 plusmn
170
89
591
56 plusmn
144
81
851
77 plusmn
374
52
Cle
aran
ce (
Lh
)55
56
plusmn 3
353
447
7 plusmn
11
9744
59
plusmn 1
211
445
4 plusmn
12
6443
60
plusmn 9
06
570
8 plusmn
19
30
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Tabl
e 2
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on
and
cle
aran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
clar
ith
rom
ycin
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
853
plusmn 4
71
647
plusmn 2
92
626
plusmn 1
79
720
plusmn 2
11
626
plusmn 1
03
633
plusmn 3
24
Cm
ax
(ng
mL)
983
73 plusmn
387
90
195
865
plusmn 8
087
21
888
23 plusmn
546
12
179
771
plusmn 6
826
11
903
31 plusmn
982
40
132
773
plusmn 4
569
5
AU
C0ndash
t (h
ng
mL)
178
793
2 plusmn
10
264
7021
322
46
plusmn 7
593
70
218
438
8 plusmn
68
812
422
037
82
plusmn 9
446
55
218
821
7 plusmn
68
163
618
359
83
plusmn 5
443
58
AU
C0ndash
inf (
hn
gm
L)20
371
17
plusmn 1
121
407
225
678
9 plusmn
77
260
623
011
87
plusmn 6
538
90
232
521
5 plusmn
95
058
323
125
29
plusmn 6
508
92
196
247
7 plusmn
52
760
2
Kel
(h
minus1 )
010
plusmn 0
04
012
plusmn 0
02
011
plusmn 0
02
012
plusmn 0
04
011
plusmn 0
02
010
plusmn 0
03
T1
2 (h
)7
87 plusmn
37
75
96 plusmn
08
86
61 plusmn
13
96
38 plusmn
15
46
45 plusmn
13
07
14 plusmn
19
4
Mea
n re
sid
ence
tim
e (h
)15
83
plusmn 5
27
131
5 plusmn
21
914
10
plusmn 1
48
142
1 plusmn
17
514
15
plusmn 1
53
146
6 plusmn
22
5A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
387
35 plusmn
324
40
210
11 plusmn
74
1722
945
plusmn 1
013
722
180
plusmn 8
876
224
16 plusmn
97
8728
661
plusmn 1
291
2
Cle
aran
ce (
Lh
)37
15
plusmn 3
058
245
6 plusmn
79
123
61
plusmn 7
29
243
1 plusmn
79
523
46
plusmn 7
30
272
4 plusmn
74
3
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Bioavailability of single oral dose of clarithromycin 79
maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)
There was no significant difference in values of AUC
0ndashinf when diets were compared with fasting for
clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin
Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C
max
AUC0ndasht
and AUC0ndashinf
are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively
A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin
Effect of fat (low vs high) on the bioavailability of clarithromycin
Cmax
AUC and Tmax
remain the same between high-fat vegetarian and non-vegetarian diets for
clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K
el also
Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin
There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T
max K
el and half-life was
observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin
Statistical evaluation (treatment effect using least square means)
Significant effect was observed for Cmax
AUC0ndasht
and AUC
0ndashinf and C
max AUC
0ndasht when fasting was compared
against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C
max p-value less
than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C
max for clarithromycin and
Cmax
AUC0ndasht
and AUC0ndashinf
for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect
Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for 14-hydroxy clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804
Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
76 Sanjay J Gurule et al
Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)
Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana
Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana
The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis
Tolerability
Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms
Product assays and in vitro dissolution testing
Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations
Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma
The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)
Pharmacokinetic methodology
WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C
max T
max and AUC
The area under the curve to the last measurable con-centration (AUC
0ndasht) was calculated by the linear trap-
ezoidal rule The area under the curve extrapolated to infinity (AUC
0ndashinf) was calculated as AUC
0ndasht + CtK
el
where Ct is the last measurable concentration The elimination rate constant (K
el) was obtained as the
slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase
Terminal half life (t12
) was calculated as 0693Kel
The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated
Statistical analysis
Statistical analysis was performed on log trans-formed pharmacokinetic parameter C
max and AUC
The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C
max AUC
0ndasht and AUC
0ndashinf SAS ver-
sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C
max AUC
0ndasht and AUC
0ndashinfin
Results
There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from
Bioavailability of single oral dose of clarithromycin 77
different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study
One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria
Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose
of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments
Tolerability
Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results
Product assays and in vitro dissolution testing
As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004
Effect of food on the bioavailability of clarithromycin
Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T
max C
max AUC
0ndasht AUC
0ndashinf K
el T
12 mean residence
time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T
max of clarithromycin in the fasting
state was 853 plusmn 471 h Tmax
observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T
max of
14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T
max was 773 plusmn 228 h for high-fat
vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T
max for
high-fat non-vegetarian diet remained the same as fasting state
An increase in Cmax
was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C
max was observed with the high-fat vegetarian diet
for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet
AUC0ndasht
also increased like Cmax
with all diets for clarithromycin and 14-hydroxy clarithromycin and
200018001600140012001000800600400200
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean ClarithromycinConcentration Versus Time
Cla
rithr
omyc
in M
ean
Con
cent
ratio
n in
Pla
sma
(ng
mL) A A Error
B B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
700
600
500
400
300
200
100
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time
14-H
ydro
xy C
larit
hrom
ycin
Mea
nC
once
ntra
tion
in P
lasm
a (n
gm
L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
78 Sanjay J Gurule et al
Tabl
e 3
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on a
nd
cea
ran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
14-h
ydro
xy c
lari
thro
myc
in
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
700
plusmn 3
25
773
plusmn 2
28
700
plusmn 2
30
813
plusmn 1
92
773
plusmn 1
98
720
plusmn 3
91
Cm
ax (
ng
mL)
421
09 plusmn
127
28
645
43 plusmn
178
65
641
22 plusmn
161
72
629
33 plusmn
119
48
625
24 plusmn
129
90
447
50 plusmn
162
76
AU
C0ndash
t (h
ng
mL)
911
705
plusmn 3
808
76
106
042
1 plusmn
26
870
710
661
42
plusmn 2
998
38
106
615
6 plusmn
27
212
210
640
11
plusmn 1
761
24
861
740
plusmn 3
038
23
AU
C0ndash
inf (
hn
gm
L)11
607
83
plusmn 5
113
51
118
320
6 plusmn
27
999
812
074
86
plusmn 3
699
03
119
605
2 plusmn
30
477
811
834
27
plusmn 2
015
23
985
924
plusmn 3
657
20
Kel
(h
minus1 )
006
plusmn 0
03
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
007
plusmn 0
02
T1
2 (h
)13
07
plusmn 6
37
900
plusmn 2
59
984
plusmn 3
08
968
plusmn 2
71
948
plusmn 1
85
105
1 plusmn
31
8
Mea
n r
esid
ence
tim
e (h
)22
66
plusmn 9
25
179
0 plusmn
34
019
01
plusmn 3
49
189
9 plusmn
33
118
77
plusmn 1
92
194
7 plusmn
42
8A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
927
76 plusmn
495
75
578
86 plusmn
224
59
607
96 plusmn
179
73
602
64 plusmn
170
89
591
56 plusmn
144
81
851
77 plusmn
374
52
Cle
aran
ce (
Lh
)55
56
plusmn 3
353
447
7 plusmn
11
9744
59
plusmn 1
211
445
4 plusmn
12
6443
60
plusmn 9
06
570
8 plusmn
19
30
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Tabl
e 2
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on
and
cle
aran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
clar
ith
rom
ycin
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
853
plusmn 4
71
647
plusmn 2
92
626
plusmn 1
79
720
plusmn 2
11
626
plusmn 1
03
633
plusmn 3
24
Cm
ax
(ng
mL)
983
73 plusmn
387
90
195
865
plusmn 8
087
21
888
23 plusmn
546
12
179
771
plusmn 6
826
11
903
31 plusmn
982
40
132
773
plusmn 4
569
5
AU
C0ndash
t (h
ng
mL)
178
793
2 plusmn
10
264
7021
322
46
plusmn 7
593
70
218
438
8 plusmn
68
812
422
037
82
plusmn 9
446
55
218
821
7 plusmn
68
163
618
359
83
plusmn 5
443
58
AU
C0ndash
inf (
hn
gm
L)20
371
17
plusmn 1
121
407
225
678
9 plusmn
77
260
623
011
87
plusmn 6
538
90
232
521
5 plusmn
95
058
323
125
29
plusmn 6
508
92
196
247
7 plusmn
52
760
2
Kel
(h
minus1 )
010
plusmn 0
04
012
plusmn 0
02
011
plusmn 0
02
012
plusmn 0
04
011
plusmn 0
02
010
plusmn 0
03
T1
2 (h
)7
87 plusmn
37
75
96 plusmn
08
86
61 plusmn
13
96
38 plusmn
15
46
45 plusmn
13
07
14 plusmn
19
4
Mea
n re
sid
ence
tim
e (h
)15
83
plusmn 5
27
131
5 plusmn
21
914
10
plusmn 1
48
142
1 plusmn
17
514
15
plusmn 1
53
146
6 plusmn
22
5A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
387
35 plusmn
324
40
210
11 plusmn
74
1722
945
plusmn 1
013
722
180
plusmn 8
876
224
16 plusmn
97
8728
661
plusmn 1
291
2
Cle
aran
ce (
Lh
)37
15
plusmn 3
058
245
6 plusmn
79
123
61
plusmn 7
29
243
1 plusmn
79
523
46
plusmn 7
30
272
4 plusmn
74
3
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Bioavailability of single oral dose of clarithromycin 79
maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)
There was no significant difference in values of AUC
0ndashinf when diets were compared with fasting for
clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin
Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C
max
AUC0ndasht
and AUC0ndashinf
are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively
A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin
Effect of fat (low vs high) on the bioavailability of clarithromycin
Cmax
AUC and Tmax
remain the same between high-fat vegetarian and non-vegetarian diets for
clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K
el also
Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin
There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T
max K
el and half-life was
observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin
Statistical evaluation (treatment effect using least square means)
Significant effect was observed for Cmax
AUC0ndasht
and AUC
0ndashinf and C
max AUC
0ndasht when fasting was compared
against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C
max p-value less
than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C
max for clarithromycin and
Cmax
AUC0ndasht
and AUC0ndashinf
for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect
Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for 14-hydroxy clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804
Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
Bioavailability of single oral dose of clarithromycin 77
different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study
One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria
Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose
of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments
Tolerability
Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results
Product assays and in vitro dissolution testing
As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004
Effect of food on the bioavailability of clarithromycin
Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T
max C
max AUC
0ndasht AUC
0ndashinf K
el T
12 mean residence
time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T
max of clarithromycin in the fasting
state was 853 plusmn 471 h Tmax
observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T
max of
14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T
max was 773 plusmn 228 h for high-fat
vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T
max for
high-fat non-vegetarian diet remained the same as fasting state
An increase in Cmax
was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C
max was observed with the high-fat vegetarian diet
for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet
AUC0ndasht
also increased like Cmax
with all diets for clarithromycin and 14-hydroxy clarithromycin and
200018001600140012001000800600400200
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean ClarithromycinConcentration Versus Time
Cla
rithr
omyc
in M
ean
Con
cent
ratio
n in
Pla
sma
(ng
mL) A A Error
B B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
700
600
500
400
300
200
100
00 5 10 15 20
Time (hr)25 30 35 40
Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time
14-H
ydro
xy C
larit
hrom
ycin
Mea
nC
once
ntra
tion
in P
lasm
a (n
gm
L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error
Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)
78 Sanjay J Gurule et al
Tabl
e 3
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on a
nd
cea
ran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
14-h
ydro
xy c
lari
thro
myc
in
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
700
plusmn 3
25
773
plusmn 2
28
700
plusmn 2
30
813
plusmn 1
92
773
plusmn 1
98
720
plusmn 3
91
Cm
ax (
ng
mL)
421
09 plusmn
127
28
645
43 plusmn
178
65
641
22 plusmn
161
72
629
33 plusmn
119
48
625
24 plusmn
129
90
447
50 plusmn
162
76
AU
C0ndash
t (h
ng
mL)
911
705
plusmn 3
808
76
106
042
1 plusmn
26
870
710
661
42
plusmn 2
998
38
106
615
6 plusmn
27
212
210
640
11
plusmn 1
761
24
861
740
plusmn 3
038
23
AU
C0ndash
inf (
hn
gm
L)11
607
83
plusmn 5
113
51
118
320
6 plusmn
27
999
812
074
86
plusmn 3
699
03
119
605
2 plusmn
30
477
811
834
27
plusmn 2
015
23
985
924
plusmn 3
657
20
Kel
(h
minus1 )
006
plusmn 0
03
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
007
plusmn 0
02
T1
2 (h
)13
07
plusmn 6
37
900
plusmn 2
59
984
plusmn 3
08
968
plusmn 2
71
948
plusmn 1
85
105
1 plusmn
31
8
Mea
n r
esid
ence
tim
e (h
)22
66
plusmn 9
25
179
0 plusmn
34
019
01
plusmn 3
49
189
9 plusmn
33
118
77
plusmn 1
92
194
7 plusmn
42
8A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
927
76 plusmn
495
75
578
86 plusmn
224
59
607
96 plusmn
179
73
602
64 plusmn
170
89
591
56 plusmn
144
81
851
77 plusmn
374
52
Cle
aran
ce (
Lh
)55
56
plusmn 3
353
447
7 plusmn
11
9744
59
plusmn 1
211
445
4 plusmn
12
6443
60
plusmn 9
06
570
8 plusmn
19
30
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Tabl
e 2
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on
and
cle
aran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
clar
ith
rom
ycin
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
853
plusmn 4
71
647
plusmn 2
92
626
plusmn 1
79
720
plusmn 2
11
626
plusmn 1
03
633
plusmn 3
24
Cm
ax
(ng
mL)
983
73 plusmn
387
90
195
865
plusmn 8
087
21
888
23 plusmn
546
12
179
771
plusmn 6
826
11
903
31 plusmn
982
40
132
773
plusmn 4
569
5
AU
C0ndash
t (h
ng
mL)
178
793
2 plusmn
10
264
7021
322
46
plusmn 7
593
70
218
438
8 plusmn
68
812
422
037
82
plusmn 9
446
55
218
821
7 plusmn
68
163
618
359
83
plusmn 5
443
58
AU
C0ndash
inf (
hn
gm
L)20
371
17
plusmn 1
121
407
225
678
9 plusmn
77
260
623
011
87
plusmn 6
538
90
232
521
5 plusmn
95
058
323
125
29
plusmn 6
508
92
196
247
7 plusmn
52
760
2
Kel
(h
minus1 )
010
plusmn 0
04
012
plusmn 0
02
011
plusmn 0
02
012
plusmn 0
04
011
plusmn 0
02
010
plusmn 0
03
T1
2 (h
)7
87 plusmn
37
75
96 plusmn
08
86
61 plusmn
13
96
38 plusmn
15
46
45 plusmn
13
07
14 plusmn
19
4
Mea
n re
sid
ence
tim
e (h
)15
83
plusmn 5
27
131
5 plusmn
21
914
10
plusmn 1
48
142
1 plusmn
17
514
15
plusmn 1
53
146
6 plusmn
22
5A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
387
35 plusmn
324
40
210
11 plusmn
74
1722
945
plusmn 1
013
722
180
plusmn 8
876
224
16 plusmn
97
8728
661
plusmn 1
291
2
Cle
aran
ce (
Lh
)37
15
plusmn 3
058
245
6 plusmn
79
123
61
plusmn 7
29
243
1 plusmn
79
523
46
plusmn 7
30
272
4 plusmn
74
3
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Bioavailability of single oral dose of clarithromycin 79
maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)
There was no significant difference in values of AUC
0ndashinf when diets were compared with fasting for
clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin
Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C
max
AUC0ndasht
and AUC0ndashinf
are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively
A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin
Effect of fat (low vs high) on the bioavailability of clarithromycin
Cmax
AUC and Tmax
remain the same between high-fat vegetarian and non-vegetarian diets for
clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K
el also
Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin
There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T
max K
el and half-life was
observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin
Statistical evaluation (treatment effect using least square means)
Significant effect was observed for Cmax
AUC0ndasht
and AUC
0ndashinf and C
max AUC
0ndasht when fasting was compared
against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C
max p-value less
than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C
max for clarithromycin and
Cmax
AUC0ndasht
and AUC0ndashinf
for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect
Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for 14-hydroxy clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804
Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
78 Sanjay J Gurule et al
Tabl
e 3
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on a
nd
cea
ran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
14-h
ydro
xy c
lari
thro
myc
in
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
700
plusmn 3
25
773
plusmn 2
28
700
plusmn 2
30
813
plusmn 1
92
773
plusmn 1
98
720
plusmn 3
91
Cm
ax (
ng
mL)
421
09 plusmn
127
28
645
43 plusmn
178
65
641
22 plusmn
161
72
629
33 plusmn
119
48
625
24 plusmn
129
90
447
50 plusmn
162
76
AU
C0ndash
t (h
ng
mL)
911
705
plusmn 3
808
76
106
042
1 plusmn
26
870
710
661
42
plusmn 2
998
38
106
615
6 plusmn
27
212
210
640
11
plusmn 1
761
24
861
740
plusmn 3
038
23
AU
C0ndash
inf (
hn
gm
L)11
607
83
plusmn 5
113
51
118
320
6 plusmn
27
999
812
074
86
plusmn 3
699
03
119
605
2 plusmn
30
477
811
834
27
plusmn 2
015
23
985
924
plusmn 3
657
20
Kel
(h
minus1 )
006
plusmn 0
03
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
008
plusmn 0
02
007
plusmn 0
02
T1
2 (h
)13
07
plusmn 6
37
900
plusmn 2
59
984
plusmn 3
08
968
plusmn 2
71
948
plusmn 1
85
105
1 plusmn
31
8
Mea
n r
esid
ence
tim
e (h
)22
66
plusmn 9
25
179
0 plusmn
34
019
01
plusmn 3
49
189
9 plusmn
33
118
77
plusmn 1
92
194
7 plusmn
42
8A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
927
76 plusmn
495
75
578
86 plusmn
224
59
607
96 plusmn
179
73
602
64 plusmn
170
89
591
56 plusmn
144
81
851
77 plusmn
374
52
Cle
aran
ce (
Lh
)55
56
plusmn 3
353
447
7 plusmn
11
9744
59
plusmn 1
211
445
4 plusmn
12
6443
60
plusmn 9
06
570
8 plusmn
19
30
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Tabl
e 2
Mea
n plusmn
SD
(st
and
ard
dev
iati
on)
of t
he
ph
arm
acok
inet
ic p
aram
eter
s vi
z T
max
C
max
A
UC
0ndasht
AU
C0ndash
inf
Kel
T
12
MR
T a
pp
aren
t vo
lum
e of
dis
trib
uti
on
and
cle
aran
ce a
fter
ad
min
istr
atio
n o
f cla
rith
rom
ycin
500
mg
XL
tab
let f
ollo
win
g fa
stin
g an
d fi
ve d
iffer
ent d
iet t
reat
men
ts (
n =
15)
for
clar
ith
rom
ycin
Fa
stin
g (A
)H
igh
-fat
ve
geta
rian
(B
)H
igh
-fat
n
on-v
eget
aria
n (
C)
Low
-fat
ve
geta
rian
(D
)L
ow-f
at
non
-veg
etar
ian
(E
)L
ow-f
at r
ice
(F)
Tm
ax (
h)
853
plusmn 4
71
647
plusmn 2
92
626
plusmn 1
79
720
plusmn 2
11
626
plusmn 1
03
633
plusmn 3
24
Cm
ax
(ng
mL)
983
73 plusmn
387
90
195
865
plusmn 8
087
21
888
23 plusmn
546
12
179
771
plusmn 6
826
11
903
31 plusmn
982
40
132
773
plusmn 4
569
5
AU
C0ndash
t (h
ng
mL)
178
793
2 plusmn
10
264
7021
322
46
plusmn 7
593
70
218
438
8 plusmn
68
812
422
037
82
plusmn 9
446
55
218
821
7 plusmn
68
163
618
359
83
plusmn 5
443
58
AU
C0ndash
inf (
hn
gm
L)20
371
17
plusmn 1
121
407
225
678
9 plusmn
77
260
623
011
87
plusmn 6
538
90
232
521
5 plusmn
95
058
323
125
29
plusmn 6
508
92
196
247
7 plusmn
52
760
2
Kel
(h
minus1 )
010
plusmn 0
04
012
plusmn 0
02
011
plusmn 0
02
012
plusmn 0
04
011
plusmn 0
02
010
plusmn 0
03
T1
2 (h
)7
87 plusmn
37
75
96 plusmn
08
86
61 plusmn
13
96
38 plusmn
15
46
45 plusmn
13
07
14 plusmn
19
4
Mea
n re
sid
ence
tim
e (h
)15
83
plusmn 5
27
131
5 plusmn
21
914
10
plusmn 1
48
142
1 plusmn
17
514
15
plusmn 1
53
146
6 plusmn
22
5A
pp
aren
t vol
um
e of
d
istr
ibu
tion
(L)
387
35 plusmn
324
40
210
11 plusmn
74
1722
945
plusmn 1
013
722
180
plusmn 8
876
224
16 plusmn
97
8728
661
plusmn 1
291
2
Cle
aran
ce (
Lh
)37
15
plusmn 3
058
245
6 plusmn
79
123
61
plusmn 7
29
243
1 plusmn
79
523
46
plusmn 7
30
272
4 plusmn
74
3
p-
valu
e le
ss th
an 0
05
ind
icat
es s
ign
ifica
nt e
ffec
t wh
en c
omp
ared
to fa
stin
g tr
eatm
ent
Bioavailability of single oral dose of clarithromycin 79
maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)
There was no significant difference in values of AUC
0ndashinf when diets were compared with fasting for
clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin
Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C
max
AUC0ndasht
and AUC0ndashinf
are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively
A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin
Effect of fat (low vs high) on the bioavailability of clarithromycin
Cmax
AUC and Tmax
remain the same between high-fat vegetarian and non-vegetarian diets for
clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K
el also
Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin
There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T
max K
el and half-life was
observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin
Statistical evaluation (treatment effect using least square means)
Significant effect was observed for Cmax
AUC0ndasht
and AUC
0ndashinf and C
max AUC
0ndasht when fasting was compared
against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C
max p-value less
than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C
max for clarithromycin and
Cmax
AUC0ndasht
and AUC0ndashinf
for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect
Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for 14-hydroxy clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804
Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
Bioavailability of single oral dose of clarithromycin 79
maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)
There was no significant difference in values of AUC
0ndashinf when diets were compared with fasting for
clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin
Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C
max
AUC0ndasht
and AUC0ndashinf
are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively
A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin
Effect of fat (low vs high) on the bioavailability of clarithromycin
Cmax
AUC and Tmax
remain the same between high-fat vegetarian and non-vegetarian diets for
clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K
el also
Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin
There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T
max K
el and half-life was
observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin
Statistical evaluation (treatment effect using least square means)
Significant effect was observed for Cmax
AUC0ndasht
and AUC
0ndashinf and C
max AUC
0ndasht when fasting was compared
against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C
max p-value less
than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C
max for clarithromycin and
Cmax
AUC0ndasht
and AUC0ndashinf
for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect
Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for 14-hydroxy clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804
Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C
max AUC
0ndasht and AUC
0ndashinf for clarithromycin
Treatment comparisonC
maxAUC
0ndashtAUC
0ndashinf
Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
80 Sanjay J Gurule et al
Pharmacokineticndashpharmacodynamic (PK-PD) analysis
Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL
Discussion
Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and
clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)
Alkhalidi et al (22) reported the arithmetic mean (SD) C
max for the test and reference formulation under
fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC
0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL
in the respective formulations The arithmetic mean T
max was 80 (56) and 61 (38) h In the fed study the
Cmax
and AUC of both formulations were significantly
Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)
2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629
High-fat non-vegetarian (C)
3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494
Low-fat vegetarian (D)
2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783
Low-fat non-vegetarian (E)
3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548
Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration
Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin
TreatmentsTime gt MIC
(0125 microgmL) in h
AUC gt MIC (0125 microgmL) in
hmicrogmLTime gt MIC
(025 microgmL) in h
AUC gt MIC (025 microgmL) in
hmicrogmLTime gt MIC
(05 microgmL) in h
AUC gt MIC (05 microgmL) in
hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)
2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081
High-fat non-vegetarian (C)
2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080
Low-fat vegetarian (D)
2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073
Low-fat non-vegetarian (E)
2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052
Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
Bioavailability of single oral dose of clarithromycin 81
increased relative to the fasting study The arithme-tic mean C
max of the two formulations was 11830
(6375) and 11996 (4963) ngmL The arithmetic mean AUC
0ndasht was 129812 (78490) and 118229
(57902) ngmiddothmL The arithmetic mean Tmax
was 57 (28) and 67 (25) h
In another study Guay et al (18) reported fasting C
max and AUC as 233 plusmn 070 microgmL and
359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C
max and AUC were 085 plusmn 027 microgmL and
142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T
max
values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin
Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C
max of 98373 plusmn 38790 ngmL
and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C
max
1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C
max value reported by
Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin
In this study the AUC0ndasht
values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC
0ndasht value reported by Alkhalidi et al under fast-
ing condition is 86029 hngmL for clarithromycinIncreases in C
max and AUC values were observed
in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C
max was observed when
clarithromycin was administered with a high-fat
vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)
There was no significant difference in values of T
max when diets were compared with fasting p-
values above 005 were observed when fasting Tmax
was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T
max values observed for both
clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting
The confidence intervals of Cmax
and AUC0ndasht
for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers
PK-PD analysis
Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
82 Sanjay J Gurule et al
clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL
Conclusion
In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C
max) and extent of absorp-
tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)
Acknowledgement
This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work
Declaration of interest The authors report no con-flict of interest
References
1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255
2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392
3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351
4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334
5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628
6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398
7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152
8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53
9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76
10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37
11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312
12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534
13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569
14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911
15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413
16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526
17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007
18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577
19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177
20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929
21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36
22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843
23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003
24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
Bioavailability of single oral dose of clarithromycin 83
tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973
25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008
26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502
27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto
28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733
29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514
Recommended