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Pharmacokinetics in Cystic Fibrosis Patients

Annual General Meeting of the Alberta Branch of the Canadian Society of Hospital Pharmacists (CSHP‐AB).

Jackson Wong, MB.BS, FRCPCH, FRCP(Edin)Jackson Wong, MB.BS, FRCPCH, FRCP(Edin)Pediatric Respirologist, University of Alberta

[email protected]

Terms of UseTerms of Use

Th t i l i thi df fil i id d tThe materials in this pdf file is provided to you

solely for personal use. It is not for distribution y p

or to be used for any other purpose without the

permission of the author.

DisclaimerDisclaimer

• The presentation is based on my personal experience and p y p popinion

• This presentation does not represent the opinion of the following organizations or committees that I serve:

– Health Canada Expert Advisory Committee in Cells, Tissues and Organs

– Canadian Society of Transplantation Standard Committee, Communication Committee

i l di i l ll b i S– International Pediatric Lung Transplant Collaborative, Secretary

– International Society of Heart and Lung Transplantation, Registry Workgroup

Goals and ObjectivesGoals and Objectives

• Discuss CF therapeutic goalsDiscuss CF therapeutic goals

• Discuss the impact of PK, drug delivery and dosing in patients with

CFCF

• Examples

I t i l id (t b i )– Intravenous aminoglycosides (tobramycin)

– Oral macrolides (azithromycin)

Inhaled antibiotics (a treonam and tobramycin)– Inhaled antibiotics (aztreonam and tobramycin)

– Pharmacokinetics of IV tobramycin in CF pre‐ and post lung transplant

Let’s Take A Closer Look

Astroham.com

General Concepts

CF Pharmokinetics

Astroham.comqbn.com

CF PharmacokineticsCF Pharmacokinetics

POTENTIAL FACTORS• Absorption

– gastric acid hypersecretion, – bile acid malabsorption – bioavailability of lipid soluble drugs– proximal small intestinal mucosal injuryproximal small intestinal mucosal injury

• Distribution– Hypoalbuminaemia ‐ reduced protein binding

H l b li i– Hypergamma‐globulinaemia – Increased volume of distribution – reduced adipose tissue, more lean mass

• Elimination– Increased renal clearance– Increased metabolic clearance

• Increased hepatic blood flow• Phase I & II hepatic biotransformation• Phase I & II hepatic biotransformation

D.J. Touw, Pharm World Sci 1998, E Ray, Clin Pharmacokinet 1998. J Prandota, Am J Ther 2011.

CF PharmacokineticsCF PharmacokineticsPOTENTIAL FACTORS

• Others

– Disease state and low FEV1

Multidrug resistance 1 (MDR1) gene polymorphism P glycoprotein (P gp)– Multidrug resistance 1 (MDR1) gene polymorphism ‐ P‐glycoprotein (P‐gp)

transmembrane ATP dependent pump

– Dose‐dependent pharmacokinetics – P‐gp capacity

– Enterohepatic recirculation of drugs

– Neonatal pharmacokinetics – tissue accumulation

– Viral infections and/or chronic inflammations and depression of metabolism

(CYP450)

D.J. Touw, Pharm World Sci 1998, E Ray, Clin Pharmacokinet 1998. J Prandota, Am J Ther 2011.

Aminoglycosides

IV Dosingg

Cell.com

TobramycinTobramycin

R id b t i id l t ti d d t• Rapid bactericidal, concentration dependent

• Inhibit bacterial protein synthesis, especially aerobic gram‐negative bacteria

• Driven by the membrane electrical potential (interior negative), it diffuses

through aqueous channels formed by porin proteins in the outer membrane ofthrough aqueous channels formed by porin proteins in the outer membrane of

gram‐negative bacteria and enter the periplasmic space

• This rate‐limiting process can be blocked or inhibited by a reduction in pH or

anaerobic conditions, as in an abscess

H.W. Taber Microbiol Rev 1987, V Braun J Infect Dis 2001, D Schlessinger CMR 1988

Elective IV Tobramycin q8 vs q24 hrsElective IV Tobramycin q8 vs q24 hrs

Rx A: q8hrs, Rx B: q24hrs IV tobramycin30 children age 11.2 yrs (1.7‐18.1)Changes in peripheral blood leukocytes, P. aeruginosa, body weight and in FEV1 after 14 days of antibiotic treatment and at 3 weeks after the end of the treatmentweeks after the end of the treatment cycle.

J. Riethmueller. Infection 2009

Elective IV Tobramycin q8 vs q24 hrsElective IV Tobramycin q8 vs q24 hrsNephrotoxicity of tobramycin was assessed by measuring first morning i t ti f N t l burine concentrations of N‐acetyl‐b‐

D‐glucosamini‐ dase (b‐NAG) and a‐1‐microglobulin and by determination of proteinuria using p gSDS‐PAGE Hearing assessed by standard audiometryNo stat significant difference in any

Urinary excretion of N‐acetyl‐b‐

No stat significant difference in any of these

Urinary excretion of N acetyl bglucosaminidase (b‐NAG) during (day 1 and 14) and after course A (day 35). logarithmic scale; box‐l t h i di 25% 75%plot showing median, 25%–75%,

minimum, maximum.

J. Riethmueller. Infection 2009

IV Aminoglycoside Pharmacokinetics1 compartment vs. 2 compartment model

• A prospective, crossover trial• CF adult patients, pseudomonas +ve• Acute pulmonary exacerbation • 3.3 mg/kg every 8 h or a single 10

mg/kg on day1mg/kg on day1• Cross over on day 2

Parameter Mean S.D. Range

Males/females 4/2 –Age (years) 29.0 4.6 23–34Height (inches) 65.5 1.3 64–68TBW (kg) 55.3 13.8 45–75

Blood samples (5 mL) were obtained from an indwelling venous catheter prior to administration, at the end of infusion, then at 10 20 30 45 60 90 120 240

TBW, total body weight; BSA, body surface area; BMI, body mass index;

( g)BSA (m2) 1.6 0.2 1.47–1.87BMI (kg/m2) 19.7 3.2 16.5–25.9CLCR (mL/min/1.73 m2) 127.0 5.8 120.6–132.9

then at 10, 20, 30, 45, 60, 90, 120, 240 and 450 min post‐dose.

An additional sample at 720 min was CLCR, creatinine clearance.

A. Aminimanizani1, JAC 02‐50‐553

obtained following the administration of the 10 mg/kg dose.

IV tobramycin q8hrs dosing


IV tobramycin q24hrs dosing


IV Aminoglycoside PharmacokineticsParameter q8h [median (interquartile range)] q24h [median (interquartile range)] P value

t½ (h) 0.54 (0.40–1.05) 0.40 (0.26–1.02) 0.39

t (h) 3 07 (2 67 5 83) 2 72 (2 22 3 70) 0 18

IV Aminoglycoside Pharmacokinetics

t½ (h) 3.07 (2.67–5.83) 2.72 (2.22–3.70) 0.18

Vc (L/kg) 0.20 (0.14–0.25) 0.16 (0.11–0.24) 0.39Vss (L/kg) 0.38 (0.26–0.46) 0.31 (0.22–0.33) 0.06CLt (mL/min/kg) 2.02 (1.37–2.46) 1.68 (1.30–2.04) 0.39CLd (mL/min/kg) 1.17 (0.49–2.44) 1.61 (0.53–2.14) 0.59AUC (mg·h/L) 97 34 (77 58–122 5) 107 7 (95 74–123 1) 0 85AUC24 (mg h/L) 97.34 (77.58–122.5) 107.7 (95.74–123.1) 0.85Cmax (mg/L) 14.0 (11.5–19.3) 35.9 (33.2–45.8) –Cmin (mg/L) 0.9 (0.8–1.2) – –C12 – 1.4 (0.8–1.5) –

t½, distribution half-life; t½

, elimination half-life; Vc, volume of central compartment; Vss, steady-state volume; CLt, total clearance;CLd, distribution clearance; AUC24, area under the curve in 24 h; Cmax, maximum serum concentration; Cmin, minimum serum concentration;C12, concentration 12 h after start of infusion.

• The distribution phase T½α of 32 and 24 min (q8h and q24h regimens) relatively long

• Distribution phase 94% competed after 4 T½α hence time for peak level @ 2 hrs• Distribution phase 94% competed after 4 T½α hence time for peak level @ 2 hrs.

• The elimination T½β of 3.1 and 2.7 h (q8h and q24h regimens) relatively short and reflect the

excellent renal function.

• No statistically significant differences in any of the PK parameter values between doses


y g y p

• A significant –ve correlation was noted between BSA and T½α with the q24h regimen (r = –0.89, P =

0.03); no similar correlation was seen with the q8h regimen.

IV Aminoglycoside Pharmacokinetics

Table 2. Model discrimination when using a one- or two-compartment model to describe the individual i

1 compartment vs. 2 compartment model

serum time curves

q8h q24h

t t t t t t t t t tone-compartment two-compartment one-compartment two-compartment

Patient r2 AIC r2 AIC r2 AIC r2 AIC

1 0.94 44.70 0.98 20.36 0.97 69.75 1.00 47.102 0.93 49.89 0.99 18.73 0.88 194.92 0.97 179.453 0.86 60.60 0.99 15.39 0.96 42.32 1.00 31.124 0.79 136.93 0.94 36.03 0.90 85.98 0.99 59.485 0.67 235.33 0.97 15.71 0.90 100.74 0.98 40.566 0 93 73 68 0 99 14 67 0 98 45 17 1 00 35 31

AIC, Akaike information criteria.

6 0.93 73.68 0.99 14.67 0.98 45.17 1.00 35.31

The pharmacokinetics of tobramycin administered either once daily or every 8 h


The pharmacokinetics of tobramycin administered either once daily or every 8 h were best described by a two‐ compartment model, as shown by the lower AIC (an information criterion) and higher r2 values

TOPIC Study Pharmacokinetic AnalysisTOPIC Study Pharmacokinetic Analysis

A Smyth. Lancet 2005

Volume of distribution k b d h dper kg body weight and age

Non‐linear regression, R2 =0.3, N=136, p<0.001)

D.J. Touw, JCF 2007

Renal elimination rate per ml/min/1.73 m2 creatinine clearance and age.

TOPIC Study Pharmacokinetic AnalysisTOPIC Study Pharmacokinetic Analysis• The Vd was significantly greater with o.d. Rx compared to t.i.d. in children. No

straightforward explanation for the difference in volume of distribution.straightforward explanation for the difference in volume of distribution.

• The elimination rate of tobramycin, for o.d., was prolonged compared with t.i.d. dosing in both children and adults

• A significant trend for a smaller Vd/kg of tobramycin with increasing age

• With a good total body clearance of tobramycin serum C largely depends on Vd• With a good total body clearance of tobramycin, serum Cpeak largely depends on Vd

• Mean Vd/kg body weight is 0.363 l/kg (Ped), 0.294 (adult), p<0.001 for the same target serum Cpeak children need on average a 20% higher dose on a mg/kg g peak g g g/ gbody weight basis compared to adults.

• Coefficient of variation of Vd/kg body weight is large (22% ped vs. 15% adult) therapeutic drug monitoring importanttherapeutic drug monitoring important.

TOPIC Study Pharmacokinetic AnalysisTOPIC Study Pharmacokinetic Analysis

• A significantly lower mean values for Kelr (ped and adult) in patient populations randomised to o.d. compared with t.i.d. administration.

• A mean rate of elimination 30% less in the population receiving q24hrs IV tobra.

• A lower Kelr (ped and adult) o.d. groups may be the result of a circadian rhythm in drug clearance caused by either

i i d– activity and rest or

– dietary protein intake or

– both combined

i h h d i i i f h i d i h d il i h l– with the administration of the active dose in the once daily group in the early evening.

Rationale of the single daily dosingRationale of the single daily dosing

1. Significant post‐antibiotic effect1. Significant post antibiotic effect

i. The duration of this effect (2‐8 hrs) depends on the height of

the preceding peak

ii. Serum level may be allowed to fall below the MIC of the

pathogen without compromising antimicrobial efficacy

iii. host factors: shortened by neutropenia, extended by ß‐lactam

antibiotic

2. Concentration dependent bactericidal action

i. Peak/MIC ratios: q24hrs dosing > q8hrs dosing

Rationale of the single daily dosingRationale of the single daily dosing

3. Saturatable uptake into renal tubule cells and the inner ear at relatively p y

low serum levels

i. Duration of exposure: may be more important determinant of toxicity than

serum levelserum level

ii. Serum troughs that at ~ 0 may shorten tissue exposure, and promote

recovery

4. Adaptive post‐exposure resistance

i. More frequent dosing tends to reduce uptake into the bacterial cell of

aerobic GNB

ii. Apparent increase in the MIC90 (i.e., reduced efficacy)

iii. Optimizing Cmax/MIC ratio may help to combat resistance ‐ in vitro pK

modelsmodels

Self AssessmentSelf Assessment

Question AnswerQuestion

• What are the pros and cons of using extended interval

Answer

Pro

• Conveniencedosing of intravenous tobramycin in patients with CF?

Convenience

• ~ more effective & less toxic

CF?Con

• Greater & more variable Vd• Lower elimination rate

• Need close monitoring

Macrolides in CF

The Biofilm Storyy

muppet.wikia.com

P. aeruginosa Senses Cell Density via QuorumS i S tSensing Systems

Quorum-sensingsignals

Activate genes involvedin biofilm development

Low bacterial density,Low [QS signal],

Little gene activation

High bacterial density,High [QS signal],Gene activation

ATS 2003

Biofilm DevelopmentBiofilm DevelopmentWhat is a Biofilm?1. A structured community of bacterial cells

enclosed in a self-produced polymeric matrix.

2. Biofilms are a protective mode of growth that allow survival in hostile environments.

3. Bacteria in biofilms are inherently resistant to killing

Planktonic bacteria(free living)

to killing.

Mature BiofilmCommunity

Extracellular matrixQuorum sensing

MicrocoloniesPili, Twitching

AttachmentFlagella, adhesins

C Fuqua & E Greenberg, Nat Rev Mol Cell Biol 2002, 3: 685‐695

Biofilm DevelopmentBiofilm Development8 days

3 days

8 hours 1.5 days

C Fuqua & E Greenberg, Nat Rev Mol Cell Biol 2002, 3: 685‐695

P. aeruginosa in CF Sputum ‐ EMP. aeruginosa in CF Sputum EM

Bacteria in clusters.

Dark matrix embedding bacteriabacteria.

R.T. Sadikot. AJRCCM 2005

The Biofilm StoryThe Biofilm Story

Green fluorescent protein as aGreen fluorescent protein as a tag for biofilm

Propidium iodide was added ft D 3 t itafter Day 3 to monitor continuously the killing of the biofilm by tobramycin

Treatment of Pseudomonas aeruginosa biofilm with Tobramycin(a) untreated wild‐type; (b) 10 μg/mL tobramycin‐treated wild‐type; (c) 20 μg/mL tobramycin‐treated wild‐type; (d) untreated ΔlasRrhlR (QS knock‐out) mutant; (e) 10 μg/mL tobramycin‐treated ΔlasRrhlR mutant; and (f) 20 μg/mL tobramycin‐treated ΔlasRrhlR mutant.

N Høiby, Int J antimicro Agents 2010

Macrolides in CFMacrolides in CF

• Disrupt the cell‐to‐cell signaling processes (quorum sensing) responsible for the formation of P d bi filPseudomonas biofilms

• Exhibit anti‐inflammatory activity through inhibition of NF‐κB and the down regulation of proinflammatory cytokines, a reduction in neutrophil accumulation and migration, and p y y , p g ,neutrophil oxidant production

• A randomized, double‐blind clinical trial conducted in CF patients chronically infected with P. aeruginosa demonstrated a significant improvement in lung function and a reduced risk ofaeruginosa demonstrated a significant improvement in lung function and a reduced risk of pulmonary exacerbations in patients receiving AZM 500 mg three times weekly over the 6‐month

• Both CFTR (CF transmembrane conductance regulator) and MDR1 are members of the ATP binding cassette family and appear to be coregulated. Upregulation of P‐glycoprotein in patients with CF may reduce the bioavailability and possibly alter the cellular accumulation of azithromycin, a known substrate for this transporter

P Beringer. Antimicrob Agents Chemother 2005

PO Azithromycin in CFPO Azithromycin in CFFour‐compartment PK model:central compartment (no. 1), peripheral compartment (no 2)peripheral compartment (no. 2), cellular compartment (no. 3), and absorptive compartment (no. 4).

b oral bolus; F bioavailability;b, oral bolus; F, bioavailability; τ, oral lag time; Ka, absorption rate constant. r(t) = IV infusion rate;

Vc volume of central compartment;Vc, volume of central compartment; Vp, volume of peripheral compartment; Vcell, volume of cellular compartment;

Tissue PBMC

Kcp and Kpc, intercompartmental rate constants between central and peripheral compartments;

Kcl and Klc, intercompartmental rate constant between central and cellular compartments;

K10, elimination rate from central compartment


Azithromycin in CFAzithromycin in CFMedian azithromycin serum concentrations versus time following a single oral (a) and a single intravenous (b)

PO

following a single oral (a) and a single intravenous (b) dose of 500 mg. Squares, healthy volunteer subjects; circles, cystic fibrosis subjects. Each value represents the median ± standard error (n = 24)

The cellular concentration‐time curve is flattened relative to the serum due to the long intracellular half‐life

IV


Azithromycin in CFAzithromycin in CF•The larger Vc in patients with CF likely represents the differences in body composition between the two groupsp g p

•Patients with CF typically have reduced adipose tissue due to malnutrition secondary to pancreatic insufficiency

•The greater amount of adipose tissue in the healthy subjects would therefore account for the more rapid (Kcp) and greater tissue distribution (larger Vp and smaller Vc) than those of the CF subjects

•The Ka and F did not differ between the two groups

•The cellular PK data demonstrateextensive accumulation within PBMCs (large Kcl/Klc ratio) with significant


( a ge c / c at o) t s g ca tintracellular binding to cell constituents (large Vcell)

Azithromycin in CFAzithromycin in CF•The intracellular concentrations were approximately 100‐fold greater than the trough serum drug concentrations (extensive cellular accumulation)

•Although the difference in Vc between the two groups was not statistically significant, CF patients exhibited a slightly larger Vc.

Therefore, the difference in K10 is likely due to a combination of a reduced clearance and larger Vc in the CF subjects

•The bioavailability and rate of absorption appear to be unaltered in CF. No alteration in dosage of AZM is necessary in patients with CF taking pancreatic enzymes

P Beringer. Antimicrob Agents Chemother 2005Tissue PBMC

E. B. Wilms. Ther Drug Monit 2006

Azithromycin in CFAzithromycin in CF



• How do oral macrolides work in CF patient?

Answer

• Disrupt the cell‐to‐cell signaling processes (quorum

• Do they need higher doses than non‐CF patients?

sensing)

• Anti‐inflammatory activity

• No

Aztreonam & eFlowAztreonam & eFlow

Aztreonam in CFAztreonam in CF

• Aztreonam is bactericidalAztreonam is bactericidal

• Inhibits mucopeptide synthesis in the bacterial cell wall,

thereby blocking peptidoglycan crosslinkingthereby blocking peptidoglycan crosslinking.

• A very high affinity for penicillin‐binding protein 3 (PBP‐3)

and mild affinity for PBP‐1a.

• Aztreonam binds the penicillin‐binding proteins of gram‐

positive and anaerobic bacteria very poorly and is largely

ineffective against them.

Neb Aztreonam in CFNeb Aztreonam in CFPlacebo AI

Adults Adolescents Adults AdolescentsCharacteristic (n¼6) (n¼6) (n¼12) (n¼11)

Median age, years (range) 34 (19–54) 16 (13–17) 31 (20–48) 15 (14–17)Sex (male:female) 3:3 3:3 7:5 5:6Race, n (%)

White 6 (100) 6 (100) 12 (100) 9 (82)Black 0 0 0 2 (18)

Genotype, n (%)yp , ( )DF508 homozygous 2 (33) 1 (17) 7 (58) 4 (36)DF508 heterozygous 3 (50) 5 (83) 5 (42) 6 (55)Other 1 (17) 0 0 1 (9)

Mean FEV1, L SD 2.31 0.71 2.85 1.11 2.36 0.59 2.58 0.72Mean FEV1, % predicted SD 67.7 12.6 79.5 20.5 66.9 17.3 88.4 16.5

AI, aztreonam lysinate for inhalation; FEV1, forced expiratory volume in 1 sec; L, liters; SD, standarddeviation.deviation.

R. L. Gibson. Ped Pulm 2006

Neb Aztreonam in CFNeb Aztreonam in CF

AI, aztreonam lysinate for inhalation; SD, standard deviation

AUC0–t, area under the plasma concentration‐time curve from pre‐dose to the last observed concentration

AUC area under the curve between plasmaAUC0–1, area under the curve between plasmaconcentration‐time curve from pre‐dose to infinity;

Cmax, maximum concentration; Tmax, time to maximum concentration; t1/2, terminal half‐life; Cl, clearance.t1/2, terminal half life; Cl, clearance.

1One patient in the AI group had an unplanned extra measurement taken 15 min post‐dose that was used in this analysis.2Calculated as ln(2) divided by the elimination rate constant (Kelim).


Aztreonam vs. Tobramycin Killing Curve1% CF sp t m 0% eight/ ol me m cinNone

nam

1% CF sputum 0% weight/volume mucin None

eb Aztreon

Ne

obramycin

Neb

To


Nebulized TOBINebulized TOBI

health.usnews.comen.wikipedia.org

Neb Tobramycin PharmacokineticsNeb Tobramycin Pharmacokinetics

D. Hubert. JCF 2009

Neb Tobramycin eFlow vs. PARI LCNeb Tobramycin eFlow vs. PARI LC

D. Hubert. JCF 2009

Tobramycin powder & T‐326 InhalerTobramycin powder & T 326 Inhaler• Low airflow resistance [approximately 0.08

(cm H2O)1⁄2/LPM] to allow patients to(cm H2O)1⁄2/LPM], to allow patients to generate high airflow rates, and in turn, attain reliable dose delivery

• inhaled volume >1.0 L, they will be able to empty more than 90% of the capsule contents

D.E. Geller. J Aerosol Med Pulm Drug Delievery 2011

Tobramycin PowderTobramycin Powder


Tobramycin PowderTobramycin Powder


Inhaled Tobramycin Powder PharmacokineticsInhaled Tobramycin Powder Pharmacokinetics

• A multi‐center, open‐label, sequential‐cohort, single‐dose, dose‐escalation study • 300 mg dose of TOBI solution for inhalation (TSI) as an active control.g ( )• Subjects were randomized to TIP or TSI in a 3:1 ratio in each of five cohorts.

TABLE 3— Sputum PK Parametersp

Parameter TIP 2 14 mg TIP 4 14 mg TIP 2 28 mg TIP 3 28 mg TIP 4 28 mg TSI 300 mg

AUC(0,1 ) (mg hr/g) 390 139 1,714 1,173 855 469 2,044 1,334 1,740 809 1,302 1,127AUC(0,12) (mg hr/g) 261 168 1,195 1,224 652 421 1,340 1,320 1,307 978 974 1,143Cmax (mg/g) 258 194 515 421 574 527 1,092 1,052 1,048 1,080 737 1,028Tmax (hr) 0.5 (0.5–0.5) 0.5 (0.5–1.0) 0.5 (0.5–4.0) 0.5 (0.5–2.0) 0.5 (0.5–1.0) 0.5 (0.5–2.0)

D.E. Geller. Ped Pulm 2007

max ( ) ( ) ( ) ( ) ( ) ( ) ( )t1/2 (hr) 0.9 0.8 1.8 0.9 1.3 1.5 0.8 0.8 2.2 1.7 1.7 1.6

Values expressed as mean SD except Tmax expressed as mean (range).

Inhaled Tobramycin Powder PharmacokineticsInhaled Tobramycin Powder Pharmacokinetics

D.E. Geller. Ped Pulm 2007



• What are the different delivery tools available for

Answer

• Pari LC Neb

• eFlowinhaled antibiotics therapy in CF patient? Are they interchangeable?

eFlow

• Powder inhaler

interchangeable?• Not interchangeable

IV Tobramycin in CF lung TransplantIV Tobramycin in CF lung Transplant

IV q8hrs Tobramycin Pre/Post Lung TransplantIV q8hrs Tobramycin Pre/Post Lung Transplant

• Retrospective studyRetrospective study

• Model: 1 compartment Bayesian method

CF & t DLT 29• CF pre‐ & post‐ DLTx, n=29

• Age mean (± SD): 26 (± 6.4) yrs

• Courses (pre/postLTx): 2: (20/16), 3: (10/8)

• Days pre/postLTx: 3‐277 / 1‐547

• Duration of Rx: 3‐14 days

• Tobramycin clearance & Vd normalized to body surface area

Dupuis, Ther Drug Monit 1999

IV q8hrs Tobramycin Pre/Post Lung TransplantIV q8hrs Tobramycin Pre/Post Lung TransplantPre‐LTx

PPo

st‐LTx




IV q8hrs Tobramycin Pre/Post Lung TransplantIV q8hrs Tobramycin Pre/Post Lung TransplantPre‐LTx Post LTx

Overall mean (± SD) tobramycin daily doses 10 4 (± 2 4) 5 1 (± 1 8)Overall mean (± SD) tobramycin daily doses

mg/kg/day

10.4 (± 2.4) 5.1 (± 1.8)

Peak level mean (± SD) μg/mL 10 3 (± 2 0) 7 1 (± 2 5)Peak level mean (± SD) μg/mL 10.3 (± 2.0) 7.1 (± 2.5)

Trough level mean (± SD) μg/mL 0.78 (± 0.51) 1.3 (± 1.5)

Dosing intervals (% total number of regimens) 8 hrs 33% 2%Dosing intervals (% total number of regimens) 8 hrs

12 hrs

24 hrs

33%

65%

2%

2%

55%

35%24 hrs

48 hrs

2%

0%

35%

6%

All significant. One‐way analysis of variance for repeated measures was used todetermine whether any differences existed in the pharmacokinetic parameters.



• Retrospective study IV 10‐12 mg/kg/24 hrsRetrospective study, IV 10 12 mg/kg/24 hrs

• 48 hrs rehydration , blood levels at 4 & 10 hrs after 3rd dose

• Model: 1 compartment modified 2 point Sawchuk Zaske method• Model: 1‐compartment, modified 2‐point Sawchuk‐Zaske method

• Tobramycin clearance = Dose/AUC

D dj t d t bt i d t t bl ( 1 / L) l l t 12 h• Doses adjusted to obtain undetectable (<1 μg/mL) level at 12 hrs

• CF pre‐ & post‐ DLTx, n=8

• Age mean (± SD): 26.3 (± 5.7) yrs

• BW, serum creatinine and creatinine clearance similar pre‐ & post LTx

Walsh, Tx Infect Dis 2011


Ke = elimination rate constant

Post LTxK ↑ 38%Ke ↑ 38%T½ ↑ 200%Cls ↓ 25%Vd ↑ IS

Walsh, Tx Infect Dis 2011

AUC IS Mean dose mg/kg/day

↓ 10.7 ± 2.5 (pre)vs. 7.6 ± 1.6 (post)



• Should post lung transplant patients receive the same

Answer

• q8hrs dosing: less +/‐ longer intervals between doses,

dose of IV tobramycin as given pre‐transplantation?

monitor closely – any period post LTx

• q24hrs dosing: less +/‐longer intervals between gdoses, monitor closely – 1st

6 weeks post LTx

ReferencesReferences 1. Touw DJ. Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis.

PharmWorld Sci 1998; 20(4):149 160PharmWorld Sci 1998; 20(4):149‐160.2. Rey E, Treluyer JM, Pons G. Drug disposition in cystic fibrosis. Clin Pharmacokinet

1998; 35(4):313‐329.3. Prandota J. Limitations in the clinical usefulness of single‐dose pharmacokinetic

studies of drugs and a bayesian approach for the estimation of kineticstudies of drugs and a bayesian approach for the estimation of kinetic parameters. Am J Ther 2004; 11(4):295‐301.

4. Smyth AR, Bhatt J. Once‐daily versus multiple‐daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev 2012; 2:CD0020092:CD002009.

5. Riethmueller J, Ballmann M, Schroeter TW, Franke P, von Butler R, Claass A et al. Tobramycin once‐ vs thrice‐daily for elective intravenous antipseudomonaltherapy in pediatric cystic fibrosis patients. Infection 2009; 37(5):424‐431.

6 Aminimanizani A Beringer PM Kang J Tsang L Jelliffe RW Shapiro BJ6. Aminimanizani A, Beringer PM, Kang J, Tsang L, Jelliffe RW, Shapiro BJ. Distribution and elimination of tobramycin administered in single or multiple daily doses in adult patients with cystic fibrosis

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