What is known and objectives
Tacrolimus is characterized by a narrow therapeutic index and a considerable inter‐ and intraindividual pharmacokinetic variability. The aim of our study was to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant of Chinese patients, identify factors especially CYP3A5*3 genetic polymorphism that explain variability, and determine dosage regimens.
Methods
Pharmacogenomic data obtained from 83 Chinese kidney transplant patients treated with tacrolimus were determined using polymerase chain reaction‐restriction fragment length polymorphism analysis. Trough blood concentration data were collected from all of the patients during the 12 months of post‐transplantation days and were analysed using the nonlinear mixed‐effects modelling program. After building the final model, 1000 bootstraps were performed to validate the final model.
Results and discussion
A one‐compartment model with first‐order absorption and elimination adequately described the pharmacokinetics of tacrolimus. In this study, we observed that POD, HCT and CYP3A5*3 genotype were determinant factors in CL/F and POD related with V/F of tacrolimus significantly. The final model with the clearance covariates was presented as: Cl/F=THETA(1)*EXP(THETA(4)*(83/POD))*(39.1/HCT)**THETA(5)*EXP(THETA(6)*CYP3A5), and the final model with the volume covariates was presented as: Vd/F=THETA(2)*POD**THETA(3). The Ka was fixed to 4.5 h−1.
What is new and conclusion
The HCT, CYP3A5*3 genetic polymorphism and POD contributed to the interindividual variability of oral tacrolimus in Chinese adult renal transplant patients.