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.
Clin Pharmacol Ther. 2024 Oct;116(4):1013-1022. doi: 10.1002/cpt.3329. Epub 2024 Jun 11.
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.
甲氨蝶呤（MTX）是一种广泛用于治疗类风湿关节炎和血液系统癌症等疾病的抗叶酸药物。本研究旨在使用基于生理的药代动力学（PBPK）模型定量解释药物转运体介导的 MTX 的药物-药物相互作用（DDI）。进行了一项开放标签、随机、4 治疗、6 序列、4 周期交叉研究，以研究利福平（RFP），一种有机阴离子转运肽 1B1/3（OATP1B1/3）抑制剂，和非布司他（FBX），一种乳腺癌耐药蛋白（BCRP）抑制剂，对健康志愿者中 MTX 药代动力学的影响。基于体外和体内数据开发了 MTX、RFP 和 FBX 的 PBPK 模型，并在临床研究中验证了最终 PBPK 模型模拟结果的性能。在临床研究中，当 MTX 与 RFP 或 FBX 联合给药时，与 MTX 单独给药相比，MTX 的全身暴露分别增加了 33%和 17%。当 MTX 与 RFP 和 FBX 联合给药时，与 MTX 单独给药相比，全身暴露增加了 52%。最终的 PBPK 模型对观察到的临床数据具有良好的预测性能。本研究中成功开发了 MTX 的 PBPK 模型，可作为一种潜在的机制模型，用于预测和评估 MTX 与其他药物的药物转运体介导的 DDI。
