Time of drug administration, CYP3A5 and ABCB1 genotypes, and analytical method influence tacrolimus pharmacokinetics: A population pharmacokinetic study

Tacrolimus (TAC) pharmacokinetics are characterized by a very high variability that complicates its therapeutic use. The aims of this study were: 1) to identify and model the effect of demographic, clinical, and genetic factors and time of drug administration on TAC pharmacokinetic variability; and 2) to assess the influence of the analytical method by modeling the TAC blood concentrations measured simultaneously by microparticle enzyme immune assay (MEIA) and liquid chromatography-tandem mass spectroscopy. Data from 19 renal transplant candidates were analyzed. A total of 266 blood samples were analyzed for TAC by both techniques. Linear regression and Bland and Altman analyses were performed to compare TAC blood concentrations obtained with MEIA and liquid chromatography-tandem mass spectroscopy. A population pharmacokinetic analysis was performed. As expected, blood concentrations obtained by MEIA were higher than those obtained by liquid chromatography-tandem mass spectroscopy. A two-compartment model with first-order absorption and elimination best fit TAC blood concentrations. An exponential model was used to describe the interindividual and interoccasion variability and a mixed model was retained for the residual variability. A supplementary proportional term was necessary for the residual error in case of TAC blood concentrations determined by MEIA. The following covariates were retained in the final model: time of drug administration on the absorption rate constant and CYP3A5 and ABCB1 genotypes on the TAC apparent clearance. All parameter estimates had reliable values. The final model was found to be stable and generated parameters with good precision. The validation of the final model by bootstrapping (2000 bootstraps), case deletion diagnostics, crossvalidation, and visual predictive check (1000 simulated subjects) gave satisfactory results. This is the first population pharmacokinetic study confirming the chronopharmacokinetics of TAC and showing an effect of ABCB1 genotype and analytical method on TAC pharmacokinetics. These results may be helpful for TAC dose individualization.