Population pharmacokinetics and pharmacogenetics of tacrolimus in healthy Chinese volunteers.

Objective: The aim of this study was to establish population pharmacokinetic models of tacrolimus in healthy Chinese volunteers.

Methods: A total of 956 tacrolimus whole blood concentrations from 73 healthy volunteers were determined using ultraperformance liquid chromatography mass spectrometry/mass spectrometry. Population pharmacokinetic analyses were performed using NONMEM. The final population pharmacokinetic models were validated with bootstrap and visual predictive check. A number of covariates were analyzed, including CYP3A5 and ABCB1 polymorphism, demographic characteristics and hematological and biological indices.

Results: The structural model was a two-compartment model with first-order absorption, and a lag time was fitted to the data. The typical population values of tacrolimus for the pharmacokinetic parameters of apparent clearance (CL/F), apparent distribution volume of the central compartment (V(2)/F), intercompartmental clearance (Q/F), apparent distribution volume of the peripheral compartment (V(3)/F), absorption rate (ka) and lag time (ALAG) were 27.7 l/h, 37.5 liters, 34.4 l/h, 357 liters, 0.795 h(-1) and 0.226 h, respectively. The interindividual variabilities of these parameters were 63.3, 62.0, 50.8, 52.3, 32.9 and 4.45%, respectively, and the intraindividual variability of observed concentrations was 14.9%. The covariates that were retained in the final models were CYP3A5 genotype on CL/F, and body surface area and red blood count on V(3)/F.

Conclusions: Population pharmacokinetic models of tacrolimus were developed in healthy volunteers. These results could provide a reference for individualized tacrolimus therapy in the clinical setting.