Pharmacokinetic modelling of enterohepatic circulation of mycophenolic acid in Malaysian lupus nephritis patients

Mycophenolic acid (MPA) is an immunosuppressant agent which is increasingly be used in treatment of lupus nephritis patients. Currently it is given as a fixed dose without drug concentration monitoring, however it is likely patients would benefit from more individualised treatment. The objective of this current study is to develop a population pharmacokinetic model of MPA in Malaysian lupus nephritis patients, such a model could then be used to assist in individualisation of therapy in the future.
Concentration-time profiles for MPA, and it major metabolite 7-O-MPA-β-glucuronide (MPAG), were collected from 25 patients on mycophenolate mofetil treatment. Blood samples for drug measurement were collected pre-dose and 1, 2, 4, 6 and 8 hours post-dose on one (n= 12) or two occasions (n= 13). During population pharmacokinetic analysis MPA and MPAG concentrations were simultaneously modelled using NONMEM 7.3. Data was logarithmically transformed and first-order conditional estimation with interaction (FOCE-I) was used throughout the model-building process.
A 2-compartment model with first-order absorption for MPA and a 1-compartment model for MPAG provided the best fit to the data. A bimodal distribution was observed for the absorption rate constant (Ka) and a mixture model for Ka was tested to describe this bimodal distribution. Enterohepatic circulation was modelled with an extra gallbladder compartment, which was continuously filled from the central compartment of MPAG. Emptying of the gallbladder compartment into the gastrointestinal compartment was assumed to occur once during the dosing interval (TGB) over a certain duration (DGB), followed by reabsorption of MPA into the central compartment. Between-subject variability was associated with MPA apparent clearance (CL/FMPA), MPA apparent central volume of distribution (Vc/FMPA), MPA apparent inter-compartmental clearance (Q/FMPA) and MPAG apparent clearance (CL/FMPAG). Between-occasion variability was included on Ka and bioavailability (F). Residual error for MPA and MPAG was adequately described by a proportional model for log-transformed data. Typical population estimates for MPA and MPAG apparent clearance (CL/FMPA and CL/FMPAG) were 14.4 L/h and 0.71 L/h, respectively.
A base model has been developed which appears to adequately characterise some of the structural and scholastic aspects of the pharmacokinetics of MPA in this study population, the influence of covariates on pharmacokinetic parameters now needs to be investigated.

Azrin Abd Rahman

  • University of Queensland