Background and objectives: Advagraf is a new extended-release once-daily formulation of tacrolimus, a potent immunosuppressant widely used in renal transplantation. The aims of his study were (i) to develop a population pharmacokinetic model for once-daily tacrolimus in adult renal transplant patients; and (ii) to develop a Bayesian estimator able to reliably estimate individual pharmacokinetic parameters and exposure indices.
Methods: Full pharmacokinetic profiles obtained from 41 adult renal transplant patients who had been switched from ciclosporin to a single daily dose of the new once-daily tacrolimus formulation for more than 6 months were analysed. Tacrolimus concentrations were measured using validated turbulent flow chromatography-tandem mass spectrometry methods. Population parameters were computed using nonlinear mixed-effect modelling software (NONMEM Version VI). The patients were randomly divided into (i) a model-building test group (n = 29); and (ii) a validation group (n = 12). Population pharmacokinetic analysis was performed to estimate the effects on tacrolimus pharmacokinetics of demographic characteristics (sex, bodyweight, age), drug interaction with prednisolone, laboratory test results (the haematocrit, haemaglobin level and serum creatinine level) and cytochrome P450 (CYP) 3A5 (CYP3A5) genetic polymorphism. The population pharmacokinetic model was further refined by taking into account all of the data from the 41 patients, and the final model was validated using a bootstrap and a visual predictive check. For Bayesian estimation, the best limited-sampling strategy was determined on the basis of the D-optimality criterion and validation performed in the validation group.
Results: The trapezoidal area under the whole-blood concentration time curve from 0 to 24 hours (AUC(24)) of tacrolimus varied by up to 50% for the same trough concentration value. The pharmacokinetics of once-daily tacrolimus were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase. The CYP3A5 genotype was the only covariate retained in the final model. The apparent clearance of tacrolimus was 2-fold higher in expressers (with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes) than in non-expressers (with the CYP3A5*3/*3 genotype). This factor explained around 25% of the interindividual variability in the apparent clearance. A posteriori Bayesian estimation allowed accurate prediction of the AUC(24) of once-daily tacrolimus, using just three sampling times (0, 1 and 3 hours post-dose) with a nonsignificant mean bias of 0.7% (range 16-20%) and good precision (root mean square error 9%).
Conclusions: Population pharmacokinetic analysis of once-daily tacrolimus in renal transplant recipients resulted in identification of the CYP3A5*1/*3 genotype as a significant covariate on the apparent clearance of tacrolimus, and the design of an accurate maximum a posteriori Bayesian estimator based on three blood concentration measurements and this covariate. Such a tool could be helpful for comparing different exposure indices or different target levels. It could contribute to improvement of the efficacy and tolerability of once-daily tacrolimus in some patients.