Doripenem vs Meropenem - UCLouvain€¦ · 02/02/2009 AstraZenaca-Advisory Board 1 Doripenem vs Meropenem: a summary of International and Belgian published data Advisory Board AstraZeneca,

02/02/2009 AstraZenaca-Advisory Board 1

Doripenem vs Meropenem: a summary of International and Belgian

published data

Advisory Board AstraZeneca, Brussels – 02/02/2009

Françoise Van Bambeke,Unité de Pharmacologie cellulaire et moléculaire

Louvain Drug Research InstituteUniversité catholique de Louvain

Brussels, Belgium


Classification of parenteral carbapenems

Group 1 Limited activity

on non-fermentative Gram(-) ErtapenemPanipenem

Group 2 Active on non-fermentative Gram(-) ImpinemMeropenemBiapenemDoripenem

Group 3 Group 2 + MRSA CS-023 (investigational)

Shah et al. CMI (2008) 14 suppl. 1 :175-180


No endocyclic SStrong binding to PBPVERY broad spectrum

Structure of the molecules

no lateral chain methyl subst.

Resistance to β-lactamases

O

O

N

S

O

OH

NH2

NCH3

HHO

CH3

ZwitterionPenetration in Gram(-), including Pseudomonas

meropenem

O

O

N

S

O

OH

NH2

NH

SNH2

OOHH

doripenem


In vitro activity


In vitro activity against selected Gram-(-) bacteria

organism Nb strains DOR MEM

Enterobacter spp 3951 0.06-0.25 ≤

0.06-0.5

E. coli 17483 ≤

0.015-0.06 ≤

0.015-0.06

ESBL (+) 886 ≤

0.06-0.03 ≤

0.06

Klebsiella spp 5920 ≤

0.06-0.125 ≤

0.06

K. pneumoniae 1625 0.03-0.25 ≤

0.03-0.12

ESBL (+) 88 0.06-0.12 0.06-0.12

Proteus mirabilis 2052 0.12-1 ≤

0.06-0.25

ESBL (+) 40 0.25 0.12

Serratia spp 619 0.25 ≤

0.06-0.125Acinetobacter spp 2974 ≥

8-32 > 8-32Pseudomonas aeruginosa 11990 0.5->8 1-16

non -S 937 16-64 > 8-32

Range of MIC90

values

1 (to 2) dilutions difference

in MIC,

most

oftenin advantage

to MEM !

Keam, Drugs (2008) 68:2021-2057


Susceptibility to resistance mechanisms

Influence of resistance

mechanisms

in Pseudomonas

carbapenem MexAB MexEF OprD metallo β-lactamase

imipenem S r / R R R

meropenem R R r R

doripenem R nd r R

R : MIC > 8 mg/Lr : MIC < 8 mg/L

Dalhoff et al., Biochem. Pharmacol. (2006) 71:1085-95


Selection of resistance in vitroMPC in Pseudomonas

Sakyo et al., J. Antibiot. (2006) 59:220-228

0.4-1.6 0.8-6.3

frequency

of resistance

selection:< 2 10-9 ~ 10-8

MIC/Cmin

> 6

Tam et al. AAC (2005) 49:4920-7


Pharmacokinetics / Pharmacodynamics


Comparative PK profile

Single dose PK

Zhanel et al., Drugs (2007) 67:1027-52

parameter DOR MEM(500 mg) (500 mg) (1g)

Cmax

(mg/L) 20.2 26 50-60

Prot. binding

(%) 8.9 2

AUC (mg.h/L) –

8 h 44.1 27.2-32.4 66.9-77.5

T

½

(h) 0.93 1


Comparative PK profile

Bolus

vs Prolonged

infusion

Kim et al., AAC (2008) 52:2497-2502Jaruratanasirikul et al., AAC (2005) 49:1337-39

parameter DOR (500 mg) MEM (1g)(Bol) (Prol) (Bol) (Prol)

Cmax

(mg/L) 23 8 112 30

AUC (mg.h/L) –

8 h 36 17 136 186

T > CMI 1 55 80 75 98T > CMI 4 27.5 55 57 73T > CMI 8 17.5 - 46 58


Doripenem

: PK/PD modeling

Bhavnani et al., AAC (2005) 49:3944-47

PK/PD in support to dosing : t > MIC ~ 35 %

1 h infusion : MIC = 2


500 mg ; q 8 h

MPC

33 % 70 %


Meropenem: PK/PD modeling

Li et al. J Clin Pharmacol. (2006) 46:1171-8

PK/PD in support to dosing : t > MIC ~ 35 %

0.5 h infusion : MIC = 8


40 % 65 %

MPC

1 g ; q 8 h


Doripenem

: PK/PD modeling

Ikawa et al., Diagn Microbiol Infect Dis. (2008) 62:292-7


0.5 h infusion : MIC = 2

Probability of target attainment rate based on Monte Carlo simulation


Meropenem

: PK/PD modeling

1 g ; q 8 h


0.5 h infusion : MIC = 1.5

Probability of target attainment rate based on Monte Carlo simulation

Li et al., J. Clin. Pharmacol (2006) 46:1171-1178


Meropenem

vs Doripenem: PD vs EUCAST bkpts

Li et al., J. Clin. Pharmacol (2006) 46:1171-1178

DOR (500 mg 3 x)

MEM(1 g 3 x)

EUCAST enterobacteriaceae 1 / 4 2 / 8

Pseudomonas 1 / 4 2 / 8

PD short infusion 2 2

PD prolonged

infusion 4 4


Meropenem

vs Doripenem: stability

for prolonged

infusion

Psathas et al., Clin Ther. (2008) 30:2075-2087 Viaene et al., AAC (2002) 46:2327-2332

DOR MEM

End of infusion 95-97 % (4h) ~ 95 % (3h)

12 h 93-95 % ~70 %

Time > 90 % (literature) > 12 h 5.15 h

(SmPC) 12 h 8 h

% of intact molecule

remaining

after

the indicated

time of incubation at

room T°


Meropenem

vs Doripenem: MICs

vs EUCAST bkpts

Pillar et al., Antimicrob Agents Chemother. 2008 52:4388-99

MIC distribution in enterobacteriacae

(USA strains)


Meropenem

vs Doripenem: MICs

vs EUCAST bkpts

Pillar et al., Antimicrob Agents Chemother. 2008 52:4388-99

MIC distribution in Pseudomonas

(USA strains)


Meropenem

vs Doripenem: MICs

vs EUCAST bkpts

ICAAC 2008 C1 088-089


(Canada)


Meropenem

vs Doripenem: MICs

vs EUCAST bkpts

ECCMID 2008 P1168; 2007 P1664; 2087


(Europe)

~ 80 %

~ 90 %

~ 80 %

~ 90 %~ 75 %

~ 90 %

~ 80 %

~ 90 %


Meropenem

: MICs

in Belgium

vs EUCAST bkpts

ICAAC 2008 C1 097

MIC distribution in Enterobacteriaceae

and Pseudomonas

~ 100 %

~ 75 %~ 85 %

What

about doripenem

?


Clinical efficacy


Respiratory

tract infections

Keam, Drugs (2008) 68:2021-2057

doripenem


Respiratory

tract infections

Sieger et al., Crit Care Med. (1997) 25: 1663-70Mouton et al., J Antimicrob Chemother. (1995) 36 Suppl A:145-56

Alvarez Lerna et al., J. Chemother. (2001) 13:70-81

study Nb patientsrandomized

Treatment

regimen Response

rate (clinical)

Response

rate (bacterio)

HAP 211MEM 1 g q8h 89 /87 * 89 / 91 *

(Cefta

2g + Tob

1mg/kg) q8h 72 / 72 * 67 / 69 *

HAP 84 MEM 1 g q8h81 73

Cefta

2 g q8h + AMK 15 mg/kg 72 76

VAP 140 MEM 1 g q8hv b82.5 74.5

Cefta

2 g q8h + AMK 15 mg/kg 66.1 53.3

* ventilated

patients (70 %)

meropenem; ~ 20 % of Pseudomonas


Respiratory

tract infections: DOR vs IMI

Chastre et al., Crit. Care Med. (2008) 36:1089-96

Microbiological

success


ICU infections: MEM

vs IMI (Belgian

study)Patient characteristics

Verwaest et al., Clin. Microbiol. Infect. (2001) 6:294-302


ICU infections: MEM

vs IMI (Belgian

study)

Clinical/microbiological

response



ICU infections: MEM

vs IMI (Belgian

study)


microbiological

response


Intra-abdominal infections : DOR

vs

MEM

Lucasti et al., Clin. Ther (2008) 30:868-83

Design

Patients with

IAI, surgical

intervention < 24 h + AB neededexclusion : uncomplicated infections

APACHE II > 30life-threatening illnessnecrotizing pancreatitis / pancreatic abcessinfection by pathogen R to one of the studied drugs

Patients profile 91 % APACHE II < 1060 % appendix; 20 % colon10 % post-operative

Treatment DOR 500 mg x 3; 1h vs MEM 1 g x 3 ; 5 minutes


Intra-abdominal infections: DOR

vs

MEM


Microbiology



vs

MEMClinical

success




vs

MEMMicrobiological

evaluation



Safety profile


Safety

-

Intra-abdominal infections



Comparative safety profile



Meropenem safety profile

Linden, Drug Saf. (2007) 30:657-68


Neurotoxicity

O

O

N

S

O

OH

NH2

RHH

binding

affinity

for GABA receptorsdepending

of (+) charge

of the side

chain

drug IC 50 (mM)

imipenem 0.5

meropenem 27.6

doripenem 50.0

X 55

X 1.8

Dalhoff et al., Biochem. Pharmacol. (2006) 71:1085-95


Meropenem safety profile

Linden, Drug Saf. (2007) 30:657-68

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Doripenem vs Meropenem - UCLouvain€¦ · 02/02/2009 AstraZenaca-Advisory Board 1 Doripenem vs Meropenem: a summary of International and Belgian published data Advisory Board AstraZeneca,