Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients

Sam, W. J., Aw, M., Quak, S. H., Lim, S. M., Charles, B. G., Chan, S. Y. and Ho, P. C. (2000) Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients. British Journal of Clinical Pharmacology, 50 6: 531-541. doi:10.1046/j.1365-2125.2000.00288.x

Author Sam, W. J.
Aw, M.
Quak, S. H.
Lim, S. M.
Charles, B. G.
Chan, S. Y.
Ho, P. C.
Title Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients
Journal name British Journal of Clinical Pharmacology
ISSN 0306-5251
Publication date 2000-12
Sub-type Article (original research)
DOI 10.1046/j.1365-2125.2000.00288.x
Volume 50
Issue 6
Start page 531
End page 541
Total pages 11
Editor L. Aarons
Place of publication London, U.K
Publisher Blackwell Science
Collection year 2000
Language eng
Subject C1
320503 Clinical Pharmacology and Therapeutics
670403 Treatments (e.g. chemicals, antibiotics)
1115 Pharmacology and Pharmaceutical Sciences
Formatted abstract
Aims  The purpose of this study was to describe the population pharmacokinetics of intravenous and oral tacrolimus (FK506) in 20 Asian paediatric patients, aged 1–14 years, following liver transplantation and to identify possible relationships between clinical covariates and population parameter estimates.

Methods  Details of drug dosage histories, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data accumulated for at least 4 days after surgery. Before analysis, patients were randomly allocated to either the population data set (n = 16) or a validation data set (n = 4). The population data set was comprised of 771 concentration measurements of patients admitted over the last 3 years. Population modelling using the nonlinear mixed-effects model (NONMEM) program was performed on the population data set, using a one-compartment model with first-order absorption and elimination. Population average parameter estimates of clearance (CL), volume of distribution (V) and oral bioavailability (F) were sought; a number of clinical and demographic variables were tested for their influence on these parameters.

Results  The final optimal population models related clearance to age, volume of distribution to body surface area and bioavailability to body weight and total bilirubin concentration. Predictive performance of this model evaluated using the validation data set, which comprised 86 concentrations, showed insignificant bias between observed and model-predicted blood tacrolimus concentrations. A final analysis performed in all 20 patients identified the following relationships: CL (l h−1) = 1.46 *[1 + 0.339 * (AGE (years) −2.25)]; V (l) = 39.1 *[1 + 4.57 * (BSA (m2)−0.49)]; F = 0.197 *[1 + 0.0887 * (WT (kg) −11.4)] and F = 0.197 *[1 + 0.0887 * (WT (kg) −11.4)]*[1.61], if the total bilirubin ≥ 200 µmol l−1. The interpatient variabilities (CV%) in CL, V and F were 33.5%, 33.0% and 24.1%, respectively. The intrapatient variability (s.d.) among observed and model-predicted blood concentrations was 5.79 ng ml−1.

Conclusions  In this study, the estimates of the pharmacokinetic parameters of tacrolimus agreed with those obtained from conventional pharmacokinetic studies. It also identified significant relationships in Asian paediatric liver transplant patients between the pharmacokinetics of tacrolimus and developmental characteristics of the patients.
© 2000 Blackwell Science Ltd
Keyword Pharmacology & Pharmacy
Liver transplantation
Population pharmacokinetics
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 28 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 10 Jun 2008, 11:39:23 EST