Türk Denise, Hanke Nina, Lehr Thorsten
Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
Pharmaceutics. 2020 Nov 10;12(11):1074. doi: 10.3390/pharmaceutics12111074.
Trimethoprim is a frequently-prescribed antibiotic and therefore likely to be co-administered with other medications, but it is also a potent inhibitor of multidrug and toxin extrusion protein (MATE) and a weak inhibitor of cytochrome P450 (CYP) 2C8. The aim of this work was to develop a physiologically-based pharmacokinetic (PBPK) model of trimethoprim to investigate and predict its drug-drug interactions (DDIs). The model was developed in PK-Sim, using a large number of clinical studies (66 plasma concentration-time profiles with 36 corresponding fractions excreted in urine) to describe the trimethoprim pharmacokinetics over the entire published dosing range (40 to 960 mg). The key features of the model include intestinal efflux via P-glycoprotein (P-gp), metabolism by CYP3A4, an unspecific hepatic clearance process, and a renal clearance consisting of glomerular filtration and tubular secretion. The DDI performance of this new model was demonstrated by prediction of DDIs and drug-drug-gene interactions (DDGIs) of trimethoprim with metformin, repaglinide, pioglitazone, and rifampicin, with all predicted DDI and DDGI and ratios within 1.5-fold of the clinically-observed values. The model will be freely available in the Open Systems Pharmacology model repository, to support DDI studies during drug development.
甲氧苄啶是一种常用抗生素，因此可能会与其他药物联合使用，但它也是多药和毒素外排蛋白（MATE）的强效抑制剂以及细胞色素P450（CYP）2C8的弱抑制剂。这项工作的目的是建立一个基于生理学的甲氧苄啶药代动力学（PBPK）模型，以研究和预测其药物相互作用（DDI）。该模型在PK-Sim中开发，使用大量临床研究（66个血浆浓度-时间曲线以及36个相应的尿排泄分数）来描述甲氧苄啶在整个已发表给药范围内（40至960毫克）的药代动力学。该模型的关键特征包括通过P-糖蛋白（P-gp）进行肠道外排、由CYP3A4进行代谢、一个非特异性肝脏清除过程以及一个由肾小球滤过和肾小管分泌组成的肾脏清除过程。通过预测甲氧苄啶与二甲双胍、瑞格列奈、吡格列酮和利福平之间的DDI以及药物-药物-基因相互作用（DDGI），证明了这个新模型的DDI性能，所有预测的DDI和DDGI以及比值均在临床观察值的1.5倍以内。该模型将在开放系统药理学模型库中免费提供，以支持药物研发过程中的DDI研究。
