Comprehensive Evaluation of OATP- and BCRP-Mediated Drug-Drug Interactions of Methotrexate Using Physiologically-Based Pharmacokinetic Modeling.

Autor: Hwang S; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.; Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Korea., Lee Y; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea., Jang Y; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea., Cho JY; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.; Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Korea.; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea., Yoon S; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.; Department of Clinical Pharmacology and Therapeutics, Seoul National University Bundang Hospital, Seongnam, Korea., Chung JY; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.; Department of Clinical Pharmacology and Therapeutics, Seoul National University Bundang Hospital, Seongnam, Korea.; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Korea.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 Oct; Vol. 116 (4), pp. 1013-1022. Date of Electronic Publication: 2024 Jun 11.
DOI: 10.1002/cpt.3329
Abstrakt: Methotrexate (MTX) is an antifolate agent widely used for treating conditions such as rheumatoid arthritis and hematologic cancer. This study aimed to quantitatively interpret the drug-drug interactions (DDIs) of MTX mediated by drug transporters using physiologically-based pharmacokinetic (PBPK) modeling. An open-label, randomized, 4-treatment, 6-sequence, 4-period crossover study was conducted to investigate the effects of rifampicin (RFP), an inhibitor of organic anionic transporting peptides (OATP) 1B1/3, and febuxostat (FBX), an inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics of MTX in healthy volunteers. PBPK models of MTX, RFP, and FBX were developed based on in vitro and in vivo data, and the performance of the simulation results for final PBPK models was validated in a clinical study. In the clinical study, when MTX was co-administered with RFP or FBX, systemic exposure of MTX increased by 33% and 17%, respectively, compared with that when MTX was administered alone. When MTX was co-administered with RFP and FBX, systemic exposure increased by 52% compared with that when MTX was administered alone. The final PBPK model showed a good prediction performance for the observed clinical data. The PBPK model of MTX was well developed in this study and can be used as a potential mechanistic model to predict and evaluate drug transporter-mediated DDIs of MTX with other drugs.
(© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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