2010 - Berlin - Germany

PAGE 2010: Applications- Other topics
Flora Musuamba-Tshinanu

An optimal designed study for population pharmacokinetic modeling and Bayesian estimation of Mycophenolic acid and Tacrolimus early after renal transplantation

FT Musuamba(1), M Mourad(2), V Haufroid(3), M De Mayer(3), Capron A(1), Delattre I(1), Verbeeck R(1), Wallemacq P(1)

(1) Louvain centre for Toxicology and Applied Pharmacology, (2) Louvain, Brussels Drud Research institute, Belgium; (3)Department of abdominal chirurgy, Cliniques Univerrsitaires Saint Luc, Brussels, Belgium

Objectives: Mycophenolic acid (MPA) and Tacrolimus (TAC) are immunosuppressive drugs used in combination with corticosteroids to prevent graft rejection after solid organ transplantation. Their pharmacokinetics (PK) are characterized by a very high unexplained variability particularly in the earlier period after transplantation. The main objective of the present work was to design a study based on D-optimality criterion to describe the PK of MPA and TAC with good precision and accuracy and to explain their variability by means of patients' demographics, biochemical tests results and physiological characteristics. Subsenquently, the study aimed to develop limited sampling models and  optimal designed Bayesian estimators for simultaneous therapeutic drug monitoring (TDM) of the 2 immunosuppressants.  

Methods: PK profiles of MPA and TAC were obtained from 65 stable renal allograft recipients on a single occasion at day 15 after transplantation. A D-optimal sampling schedulethe was selected using popED software  based on previously published studies parameters values for MPA and TAC. Population PK models were developped for TAC and MPA using NONMEM and subsequently limited sampling formulas and Bayesian estimators were developped for the simultaneous TDM of these drugs.

Results: Optimal samplig times were estimated to be at , 0.02, 0.24, 0.64, 0.98 1.37, 2.38 and 11 h after oral drugs intake. The best population PK models to describe MPA and TAC concentrations were two compartment models with first order elimination. A first order absorption with lag time and a transit comparment model best described TAC and MPA absorption respectively. Prameters were estimated with good precision and accuracy. Whilst hematocrit lebels and CYP3A5 genetic polymorphism significantly influenced TAC clearance, the pharmaceutical formulation(mofetil ester or enteric coated sodium salt) and MPR2 polymorphism were found to influence MPA absorption and elimination respectively. Limited sampling formulas and Bayesian estimators including optimal sampling times were subsequently developped and validated by bootstrapping and external validation.  

Conclusions: The prospective use of simulteneous optimal design approach for MPA and TAC has allowed good estimation of their PK parameters in the early period after transplantation, wich is characterised by a very high unexplained variability. The influence of some covariates could be shown and limited sampling formulas and optimal designed Bayesian estimators could be devlopped for the simultaneous TDM of these drugs.


Reference: PAGE 19 (2010) Abstr 1927 [www.page-meeting.org/?abstract=1927]
Poster: Applications- Other topics