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

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-b-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. AIMThis study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODSMPA 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-b-glucuronide (MPAG) concentrations using nonlinear mixed effect modelling. RESULTSPK 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 Ϯ SD disease duration was 3.8 Ϯ 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

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

“…Last, population PK/PD modeling can also be used as a basis for Bayesian forecasting, whereby prior population PK/PD data can be updated with individual patient data to optimize dosing, particularly for drugs with complex disposition . For example, a population PK model was developed to characterize the PK of mycophenolic acid in children with systemic lupus, accounting for enterohepatic recirculation . Because weight‐based dosing of mycophenolate in systemic lupus does not accurately predict exposure to the active metabolite, future efforts may use the population PK model in conjunction with a Bayesian estimator to individualize mycophenolate dosing .…”

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans

“…Various models for EHC have been developed (8,(24)(25)(26)(27)(28), including physiologically based PK models with EHC (61)(62)(63). These models either assumed continuous enterohepatic recirculation (25,(40)(41)(42), one or multiple secretions of bile using an on/off switch (i.e., "lag-time(s)") (24,26,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58) or implemented a sine function to describe periodic bile releases (27,28,59,60).…”

“…These models typically describe the time of onset of EHC by a single on/off switch (i.e., a "lag-time") (26) or characterize the periodic time-course of EHC via a sine function (27,28). To our knowledge, all published models only characterized EHC in one species and did not fit plasma concentration time profiles in the presence of EHC after multiple dosing.…”

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

“…which involved healthy subjects, 5 studies used data collected from pediatric patients with SLE and 11 published papers included PK studies from adult patients. Some studies established an EHC model that combines MPA and MPAG simultaneously based on physiological aspects or biliary excretion [43,46–48]. A constant represents the rate of filling the gallbladder from the central compartment.…”

“…Sherwin et al . developed a six-compartment model including a gallbladder compartment with first-order absorption and a single series of transit compartments in pediatric and adolescent patients with cSLE [48]. Compared with conventional empirical models, this population PK model incorporates physiological aspects associated with MPA disposition successfully, contributing to optimally individualized drug therapy.…”