Tacrolimus population pharmacokinetics in adult heart transplant patients.

Introduction: Tacrolimus is an immunosuppressant largely used in heart transplantation. However, the calculation of its exposure based on the area under the curve (AUC) requires the use of a population pharmacokinetic (PK) model. The aims of this work were (i) to develop a population PK model for tacrolimus in heart transplant patients, (ii) to derive a maximum a posteriori Bayesian estimator (MAP‐BE) based on a limited sampling strategy (LSS) and (iii) to estimate probabilities of target attainment (PTAs) for AUC and trough concentration (C0). Material and Methods: Forty‐seven PK profiles (546 concentrations) of 18 heart transplant patients of the Pharmacocinétique des Immunosuppresseurs chez les patients GREffés Cardiaques study receiving tacrolimus (Prograf®) were included. The database was split into a development (80%) and a validation (20%) set. PK parameters were estimated in MONOLIX® and based on this model a Bayesian estimator using an LSS was built. Simulations were performed to calculate the PTA for AUC and C0. Results: The best model to describe the tacrolimus PK was a two‐compartment model with a transit absorption and a linear elimination. Only the CYP3A5 covariate was kept in the final model. The derived MAP‐BE based on the LSS (0‐1‐2 h postdose) yielded an AUC bias ± SD = 2.7 ± 10.2% and an imprecision of 9.9% in comparison to the reference AUC calculated using the trapezoidal rule. PTAs based on AUC or C0 allowed new recommendations to be proposed for starting doses (0.11 mg·kg−1·12 h−1 for the CYP3A5 nonexpressor and 0.22 mg·kg1·12 h−1 for the CYP3A5 expressor). Conclusion: The MAP‐BE developed should facilitate estimation of tacrolimus AUC in heart transplant patients. [ABSTRACT FROM AUTHOR]