Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients

Aims The purpose of this study was to describe the population pharmacokinet ics of intravenous and oral tacrolimus (FK506) in 20 Asian paediatric patie nts, aged 1-14 years, following liver transplantation and to identify possi ble relationships between clinical covariates and population parameter esti mates. Methods Details of drug dosage histories, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring da ta accumulated for at least 4 days after surgery. Before analysis, patients were randomly allocated to either the population data set (n = 16) or a va lidation data set (n = 4). The population data set was comprised of 771 con centration measurements of patients admitted over the last 3 years. Populat ion modelling using the nonlinear mixed-effects model (NONMEM) program was performed on the population data set, using a one-compartment model with fi rst-order absorption and elimination. Population average parameter estimate s of clearance (CL), volume of distribution (V) and oral bioavailability (F ) were sought; a number of clinical and demographic variables were tested f or their influence on these parameters. Results The final optimal population models related clearance to age, volum e of distribution to body surface area and bioavailability to body weight a nd total bilirubin concentration. Predictive performance of this model eval uated using the validation data set, which comprised 86 concentrations, sho wed insignificant bias between observed and model-predicted blood tacrolimu s concentrations. A final analysis performed in all 20 patients identified the following relationships: CL (1 h(-1)) = 1.46 *[1 + 0.339 * (AGE (years) -2.25)]; V (1) = 39.1 *[1 + 4.57 * (BSA (m(2)) - 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 greater than or equal to 200 mu mol 1(-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 mod el-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 l iver transplant patients between the pharmacokinetics of tacrolimus and dev elopmental characteristics of the patients.