Mycophenolic acid (MPA) and its metabolites in kidney transplant recipients: a semi-mechanistic enterohepatic circulation model to improve estimating exposure

摘要

Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of EHC in their modeling assumptions. The aim of this study was i) to develop an integrated model of MPA (total and unbound) and its metabolites (MPAG and Acyl-MPAG) in kidney recipients, where this model provides a more physiological representation of EHC process, and ii) to evaluate the effect of donor and recipient clinical covariates and genotypes on MPA disposition. A five-compartment model with first-order input into an unbound MPA compartment connected to the MPAG, acyl-MPAG, and gallbladder compartment best fit the data. To represent the EHC process, the model was built based on the physiological concepts related to the hepatobiliary system and the gallbladder filling and emptying processes. The effect of cyclosporine versus tacrolimus on clearance of unbound MPA was included in the base model. Covariate analysis showed creatinine clearance to be significant on oral clearance of unbound MPA. The hepatic nuclear factor 1 alpha (HNF1A) genetic single nucleotide polymorphism (SNP) (rs2393791) in the recipient significantly affected the fraction of enterohepatically-circulated drug. Oral clearance of MPAG was affected by recipient IMPDH1 SNP (rs2288553), diabetes at the time of transplant, and donor sex.