Population pharmacokinetics of mycophenolic acid and dose optimization with limited sampling strategy in liver transplant children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Population pharmacokinetic data for mycophenolic acid (MPA) have been reported in adult and paediatric kidney transplant recipients but not in paediatric liver transplant recipients. • MPA AUC during a dosage interval (AUC(0,12 h) is routinely used to optimize mycophenolate mofetil (MMF) dosages in solid organ transplant recipients. WHAT THIS STUDY ADDS • This study describes MPA population pharmacokinetics in paediatric liver transplant recipients for the first time. • The age of the children and the time elapsed since the transplantation were found to affect MPA pharmacokinetics significantly, mainly the apparent volume of distribution. • The limited sampling strategy chosen to estimate individual MPA AUC(0,12 h) with concentrations measured 0, 1 and 4 h after MMF administration may be useful to optimize child care during the post transplantation period. AIMS The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h). METHODS Twenty‐eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model‐building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (ka), the apparent volume of distribution (V/F) and apparent clearance (CL/F). RESULTS Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. ka, estimated at 1.7 h−1 at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h−1. To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II® software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did