Abstract
Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and is under investigation for its efficacy against osteosarcoma. We investigated the genetic variability of whole-exome sequencing (WES) data from 15 osteosarcoma patients who receive mycophenolate mofetil (MMF), a prodrug of MPA. Using whole-exome sequencing (WES), we found 48 variants from the 15 genes which are related to MPA and its metabolite (MPAG) metabolism. Three variants were found to significantly correlate with the pharmacokinetic parameters of MPA after single-dose MMF administration including SLCO1B3 (rs4149117, T>G), SLCO1B1 (rs2306283, A>G) and ABCG2 (rs2231142, G>T). Moreover, five variants were found to significantly correlate with the pharmacokinetic parameters of MPA after multiple doses of MMF administration (at steady state) including SLCO2B1 (rs2306168, C>T), ABCG2 (rs2231137, C>T), UGT1A8 (rs3755323, T>C), UGT1A8 (rs3755321, T>C) and UGT1A8 (rs4148323, G>A). All of these variants are missense mutations. In addition, in this study, we could build the population pharmacokinetic models for MPA in Thai osteosarcoma patients and healthy volunteers, which include genetic covariates. It was found that the pharmacokinetics of MPA in both populations can be described by a two-compartment pharmacokinetic model with 1st order drug elimination. Furthermore, the addition of the absorption lag time in the model for drug absorption following multiple doses of MMF (steady state) could significantly reduce the objective function value. Based on the population pharmacokinetic study, genetic factors affecting the pharmacokinetic parameters of MPA have not been identified. Based on the results of this population pharmacokinetic study, the pharmacokinetic parameters of MPA are different between healthy volunteers and osteosarcoma patients. Osteosarcoma patients had lower CL/F and Vc/F of MPA compared to healthy volunteers. Moreover, in osteosarcoma patients, it was also found that MPA pharmacokinetic parameters differed between post-administration of MMF in a single dose and multiple doses (steady state). After a single dose of MMF administration, the CL/F and Vc/F of MPA were approximately 2-fold and 1.4-fold higher than after multiple doses of MMF administration (steady state), respectively.
