Development of Population PK Model with Enterohepatic Circulation for Mycophenolic Acid in Patients with Childhood-Onset Systemic Lupus Erythematosus

Document Type

Article

Publication Date

5-2012

Abstract

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.

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 CL1/F 25.3 l h–1, V3/F 20.9 l, V4/F 234 l and CL2/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.

DOI

10.1111/j.1365-2125.2011.04140.x

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