Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co‐treated with tacrolimus: A population analysis

WHAT IS KNOWN AND OBJECTIVE: Mycophenolate mofetil, an ester prodrug of mycophenolic acid (MPA), is widely used to prevent graft rejection after kidney transplantation. The pharmacokinetic (PK) of MPA has been extensively studied, which revealed a high degree of variability. An integrated population PK (PopPK) model of MPA and its main metabolite mycophenolic acid glucuronide (MPAG) was developed using the adult patients who underwent kidney transplant and were administered oral mycophenolate mofetil combined with tacrolimus. METHODS: In total, 917 MPA and 740 MPAG concentrations in191 adult patients were analysed via nonlinear mixed-effects modelling. The concentration-time data were adequately described using a chain compartment model, including central and peripheral compartments for MPA and a central compartment for MPAG. Stepwise forward inclusion and backward elimination procedures were used to investigate the effects of genetic polymorphisms, including in UGT1A8, UGT1A9, UGT2B7, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, and HNF1α. RESULTS AND DISCUSSION: These genetic polymorphisms in metabolic enzymes and transporters have no obvious impact on the PK of MPA in adult patients who underwent kidney transplant and were co-treated with tacrolimus. The post-transplant time, serum albumin, and creatinine clearance were identified as significant covariates affecting the PK of MPA and MPAG, which should be considered in the clinical use of mycophenolate mofetil. WHAT IS NEW AND CONCLUSION: We established a PopPK model of MPA and MPAG in Chinese adult patients who underwent kidney transplant and were co-treated with tacrolimus. Genetic polymorphisms in metabolic enzymes and transporters showed no obvious impact on MMF PK. A model-informed dosing strategy was proposed by the established model, and MMF dose adjustment should be based on ALB levels and the post-transplantation time.