Development of population PK model with enterohepatic circulation for mycophenolic acid in patients with childhood-onset systemic lupus erythematosus.

Aim: This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE).
Methods: MPA concentration-time data were from outpatients on stable oral mycophenolate mofetil (MMF) and collected under fasting conditions, with standardized meals (1 and 4 h post-dose). Sampling times were pre-dose, 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 9 h, post dose. The population PK analysis simultaneously modelled MPA and 7-O-MPA-β-glucuronide (MPAG) concentrations using nonlinear mixed effect modelling.
Results: PK analysis included 186 MPA and MPAG concentrations (mg l(-1)) from 19 patients. cSLE patients, age range 10-28 years, median 16.5 years were included. Mean ± SD disease duration was 3.8 ± 3.7 years. The final PK model included a gallbladder compartment for enterohepatic recycling and bile release time related to meal times, with first order absorption and single series of transit compartments. The PK estimates for MPA were CL(1) /F 25.3 l h(-1), V(3) /F 20.9 l, V(4) /F 234 l and CL(2) /F 19.8 l h(-1).
Conclusion: The final model fitted the complex processes of absorption and enterohepatic circulation (EHC) in those treated with MMF for cSLE and could be applied in Bayesian dose optimization algorithms.
(© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)