Population pharmacokinetic analysis of factors affecting the clearance of methotrexate polyglutamates in red blood cells in Japanese patients with rheumatoid arthritis

Objectives 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 using population pharmacokinetic analysis. Methods A total of 268 Japanese rheumatoid arthritis patients receiving low-dose MTX therapy were included. RBC MTX-PGs concentrations were measured using liquid chromatography–tandem mass spectrometry. Patient characteristics, including genetic polymorphisms in transporters (reduced folate carrier 1 (RFC1), ATP binding cassette subfamily B member 1 (ABCB1), ATP-Binding Cassette sub-Family C Member 2 (ABCC2), and ATP-binding transporter cassette subfamily G member 2 (ABCG2)) and enzymes (folylpolyglutamyl synthase and γ-glutamyl hydrolase) related to MTX metabolism, were evaluated as covariates. Population pharmacokinetic analysis was performed using Phoenix NLME software. Results The final population pharmacokinetic model identified body weight, estimated glomerular filtration rate, and proton pump inhibitor co-administration as covariates for CL/F of total RBC MTX-PGs. Lower body weight, a lower estimated glomerular filtration rate, and proton pump inhibitor use were associated with decreased CL/F. Genetic polymorphisms were not identified as significant covariates for CL/F in this study. Conclusions Body weight, estimated glomerular filtration rate, and proton pump inhibitor co-administration may influence the CL/F of total RBC MTX-PGs in Japanese patients with rheumatoid arthritis. These findings may support a model-informed interpretation of RBC MTX-PGs concentrations, although further studies are needed to confirm the clinical applicability of the model.