Population Pharmacokinetics and Bayesian Estimation of Mycophenolic Acid Exposure in Heart Transplant Recipients: Comparison of Two Approaches

Abstract

Purpose Mycophenolic acid (MPA) area under the curve (AUC) has been reported as an important marker of graft outcome. The aim of our study was to develop: (i) population pharmacokinetic (POPPK) models in adult heart transplant patients using a parametric (P) and a nonparametric (NP) approach; and (ii) two independent Bayesian estimators (BE) enabling AUC determination using a limited sampling strategy. Methods and Materials Fifty-six MPA pharmacokinetic (PK) profiles were collected from 39 adult heart transplant patients given mycophenolate mofetil. POPPK analysis was performed using both the parametric iterative two-stage Bayesian method and the nonparametric adaptive grid approach (using Pmetrics R package). The PK profiles were fitted to a one-compartment model with first-order elimination combined to two gamma laws to describe the absorption phase. Results PK profiles were divided into a development dataset (n=37) and a validation dataset (n=19). For each approach, a POPPK model was developed that accurately fitted the observed data. In the validation group, the BE developed using each model yielded good AUC estimation performance (bias of -1.26±19.33% (P) and -1.12±19.34% (NP)) on the basis of a 20, 60, 180 and 360 minutes sampling schedule. Accordingly, dose adjustment (for a 45 mg.h/L target AUC) based on BE was similar to that proposed on the basis of the reference AUC (trapezoidal AUC using all the available concentrations) in 79% (P) and 84% (NP) of the patients. Conclusions The PK profiles of MPA in heart transplant patients are more complex than those observed in kidney graft recipients. Bayesian estimators allowing the determination of MPA AUC using a limited number of blood samples have been developed using 2 totally independent population modelling approaches, the combination of which now increase the accuracy of our results. They are now available on our ISBA website (https://pharmaco.chu-limoges.fr) for routine dose adjustment.