Population Pharmacokinetic Analysis of Factors Affecting the Clearance of Methotrexate Polyglutamates in Red Blood Cells in Japanese Patients with Rheumatoid Arthritis.

To examine factors affecting the apparent clearance (CL/F) of total methotrexate polyglutamates (MTX-PGs) in red blood cells (RBCs) in Japanese patients with rheumatoid arthritis (RA) using population pharmacokinetic analysis. A total of 268 Japanese RA patients receiving low-dose MTX therapy were included. RBC MTX-PGs concentrations were measured using LC-MS/MS. Patient characteristics, including genetic polymorphisms in transporters (RFC1, ABCB1, ABCC2, ABCG2) and enzymes (FPGS, GGH) related to MTX metabolism, were evaluated as covariates. Population pharmacokinetic analysis was performed using Phoenix NLME software. The final population pharmacokinetic model identified body weight (BW), estimated glomerular filtration rate (eGFR), and proton pump inhibitor (PPI) co-administration as covariates for CL/F of total RBC MTX-PGs. Lower BW, lower eGFR, and PPI use were associated with decreased CL/F. Genetic polymorphisms were not identified as significant covariates for CL/F in this study. BW, eGFR, and PPI co-administration may influence the CL/F of total RBC MTX-PGs in Japanese patients with RA. These findings may support model-informed interpretation of RBC MTX-PGs concentrations, although further studies are needed to confirm the clinical applicability of the model.