Population pharmacokinetic-pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period.

AimThe purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK-PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period. MethodsA total of 214 MPA plasma concentrations-time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n=97) in peripheral blood mononuclear cells were available for PK-PD modelling. The PK-PD model was developed using non-linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK-PD model using post hocBayesian PK parameter estimates. Covariate analysis included patient demographics, co-medication and clinical laboratory data. Non-parametric bootstrapping and prediction-corrected visual predictive checks were performed to evaluate the final models. ResultsA two compartment model with a transit compartment absorption best described MPA PK. A non-linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) lh(-1) 70kg(-1); V-c/F, 45.4 (29.6, 55.6) l; V-p/F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) lh(-1); K-a, 2.5 (1.45, 4.93)h(-1). Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory E-max model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK-PD parameter estimates (and their 95% confidence intervals) were: E-0, 3.45 (2.61, 4.56) nmolh(-1)mg(-1) protein and EC50, 1.73 (1.16, 3.01) mgl(-1). E-max was fixed to 0. There were two African-American patients in our study cohorts and both had low IMPDH baseline activities (E-0) compared with Caucasian patients (mean value 2.13mgl(-1)vs. 3.86mgl(-1)). ConclusionAn integrated population PK-PD model of MPA has been developed in paediatric renal transplant recipients. The current model provides information that will facilitate future studies and may be implemented in a Bayesian algorithm to allow a PK-PD guided therapeutic drug monitoring strategy.