Development of population PK model with enterohepatic circulation for mycophenolic acid in patients with childhood-onset systemic lupus erythematosus
Article first published online: 5 APR 2012
© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 73, Issue 5, pages 727–740, May 2012
How to Cite
Sherwin, C. M. T., Sagcal-Gironella, A. C. P., Fukuda, T., Brunner, H. I. and Vinks, A. A. (2012), Development of population PK model with enterohepatic circulation for mycophenolic acid in patients with childhood-onset systemic lupus erythematosus. British Journal of Clinical Pharmacology, 73: 727–740. doi: 10.1111/j.1365-2125.2011.04140.x
- Issue published online: 5 APR 2012
- Article first published online: 5 APR 2012
- Accepted manuscript online: 7 NOV 2011 03:55AM EST
- Received; 23 September 2010; Accepted; 30 October 2011; Accepted Article Published Online; 7 November 2011
- childhood-onset systemic lupus erythematosus;
- enterohepatic circulation;
- mycophenolic acid;
- population pharmacokinetics
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Despite its increased use, the pharmacokinetics (PK) of mycophenolic acid (MPA) and the relationship between dose, plasma concentration and exposure are poorly understood, especially in children.
• The PK of MPA are associated with high inter- and intra-individual variability.
• MPA and its metabolites, like the inactive 7-O-MPA-β-glucuronide (MPAG) undergo enterohepatic circulation (EHC), which can contribute to an increase in exposure to MPA of 40% (range 10–60%).
WHAT THIS STUDY ADDS
• Thisis the first report of MPA PK in adolescents with childhood-onset systemic lupus erythematosus (cSLE).
• The proposed final population PK model successfully incorporates the physiological aspects associated with MPA disposition, which includes MPA and its main metabolite MPAG, and adequately reflects the complex processes of absorption and enterohepatic circulation associated with mycophenolate mofetil (MMF) oral dosing in patients with cSLE.
• This model provides a basis for further development of a model-based Bayesian estimator for individualized MPA dosing in paediatric patients treated for cSLE.
This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE).
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.
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 CL1/F 25.3 l h–1, V3/F 20.9 l, V4/F 234 l and CL2/F 19.8 l h–1.
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.