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

Aim The 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. Methods A 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 hoc   B ayesian 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. Results A 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) l h −1 70 kg −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) l h −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) nmol h −1  mg −1 protein and E C 50 , 1.73 (1.16, 3.01) mg l −1 . E max was fixed to 0. There were two A frican‐ A merican patients in our study cohorts and both had low IMPDH baseline activities ( E 0 ) compared with C aucasian patients (mean value 2.13 mg l −1 vs. 3.86 mg l −1 ). Conclusion An 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 B ayesian algorithm to allow a PK−PD guided therapeutic drug monitoring strategy.