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 4h post-dose). Sampling times were pre-dose, 20, 40min, 1, 1.5, 2, 3, 4, 6 and 9h, 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 (mgl ^-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 25.3lh ^-1, V ₃/F 20.9l, V ₄/F 234l and CL ₂/F 19.8lh ^-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.