Population pharmacokinetic-pharmacogenetic model of tacrolimus in the early period after kidney transplantation

Abstract

As tacrolimus has a rather narrow therapeutic range and high individual variability in its pharmacokinetics, it is important to determine the cause of the variation in tacrolimus pharmacokinetics. The purpose of this study was to establish a population pharmacokinetic-pharmacogenetic model of tacrolimus and identify covariates that affect pharmacokinetic parameters to prevent fluctuations in the tacrolimus trough concentration during the early period after transplantation. Data from 1501 trough concentrations and 417 densely collected concentrations were compiled from 122 patients who were on post-operative days 10-20 and analysed with a nonlinear mixed-effect model. The first-order conditional estimation (FOCE) with interaction method was used to fit the model using the NONMEM program. Clinical/laboratory data were also collected for the same period, and CYP3A5 and ABCB1 genotypes were analysed for use in modelling from all included patients. An empirical Bayesian approach was used to estimate individual pharmacokinetic profiles. A one-compartment model with first absorption and elimination and lag time best described the data. The estimated population mean of clearance (CL/F), volume of distribution (V/F) and absorption rate (Ka ) were 21.9 L/hr, 205 L, and 3.43/hr, respectively, and the lag time was fixed at 0.25 hr. Clearance increased with days after transplantation and decreased with CYP3A5*3/*3 about 18.4% compared with CYP3A5*1 carriers (p < 0.001). A population pharmacokinetic model was developed for tacrolimus in early post-kidney transplantation recipients to identify covariates that affect tacrolimus pharmacokinetics. Post-operative days and CYP3A5 genotype were confirmed as critical factors of tacrolimus pharmacokinetics.