Clinical Pharmacokinetics and Bayesian Estimators for the Individual Dose Adjustment of a Generic Formulation of Tacrolimus in Adult Kidney Transplant Recipients.

BACKGROUND Tacrolimus has a narrow therapeutic range and requires dose adjustment, usually based on the trough blood concentration but preferably on the area under the concentration-time curve over 12 h post-dose (AUC0-12h). The single-arm, multicentre, clinical study IMPAKT aimed: (i) to develop, in de novo kidney transplant recipients, pharmacokinetic models and maximum a-posteriori Bayesian estimators for a generic, immediate-release, oral formulation of tacrolimus to estimate tacrolimus AUC0-12h at different post-transplant periods using a limited sampling strategy, and considering the CYP3A5*3 polymorphism as a covariate and (ii) to compare the performance of these Bayesian estimators to those previously developed for the original formulation. METHODS Thirty patients were enrolled and 29 provided nine blood samples over 9 h at day 7 and months 1 and 3 post-transplant. Tacrolimus blood profiles measured with liquid chromatography-tandem mass spectrometry were modelled using one-compartment, double gamma absorption, linear elimination models developed in-house. Different limited sampling strategies of three time-points within 4 h post-dose were tested for the maximum a-posteriori Bayesian estimator of tacrolimus AUC0-12h. The models and estimators were validated internally and their performance compared to that of models previously developed for the original formulation. RESULTS The concentration-time curves, AUC0-12h/dose and trough blood concentration/dose exhibited wide inter-individual variability. The covariate-free pharmacokinetic models developed for the three post-transplant periods closely fitted the individual profiles. Maximum a-posteriori Bayesian estimators based on three different limited sampling strategies and no covariate yielded accurate AUC0-12h estimates, including for the five cytochrome P450 3A5 expressers and for the four patients without corticosteroids. The 0-1 h-3 h strategy finally chosen had very low bias (- 4.0 to - 2.5%) and imprecision (root mean square error 5.5-9.2%). The maximum a-posteriori Bayesian estimators previously developed for the reference product fitted the generic profiles with similar performance. CONCLUSIONS We developed original pharmacokinetic models and accurate maximum a-posteriori Bayesian estimators to estimate patient exposure and adjust the dose of generic tacrolimus, and confirmed that the robust tools previously developed for the original formulation can be applied to this generic.