BACKGROUND Metformin is a widely prescribed antidiabetic BCS Class III drug (low permeability) that depends on active transport for its absorption and disposition. It is recommended by the US Food and Drug Administration as a clinical substrate of organic cation transporter 2/multidrug and toxin extrusion protein for drug-drug interaction studies. Cimetidine is a potent organic cation transporter 2/multidrug and toxin extrusion protein inhibitor. OBJECTIVE The objective of this study was to provide mechanistic whole-body physiologically based pharmacokinetic models of metformin and cimetidine, built and evaluated to describe the metformin-SLC22A2 808G>T drug-gene interaction, the cimetidine-metformin drug-drug interaction, and the impact of renal impairment on metformin exposure. METHODS Physiologically based pharmacokinetic models were developed in PK-Sim® (version 8.0). Thirty-nine clinical studies (dosing range 0.001-2550 mg), providing metformin plasma and urine data, positron emission tomography measurements of tissue concentrations, studies in organic cation transporter 2 polymorphic volunteers, drug-drug interaction studies with cimetidine, and data from patients in different stages of chronic kidney disease, were used to develop the metformin model. Twenty-seven clinical studies (dosing range 100-800 mg), reporting cimetidine plasma and urine concentrations, were used for the cimetidine model development. RESULTS The established physiologically based pharmacokinetic models adequately describe the available clinical data, including the investigated drug-gene interaction, drug-drug interaction, and drug-drug-gene interaction studies, as well as the metformin exposure during renal impairment. All modeled drug-drug interaction area under the curve and maximum concentration ratios are within 1.5-fold of the observed ratios. The clinical data of renally impaired patients shows the expected increase in metformin exposure with declining kidney function, but also indicates counter-regulatory mechanisms in severe renal disease; these mechanisms were implemented into the model based on findings in preclinical species. CONCLUSIONS Whole-body physiologically based pharmacokinetic models of metformin and cimetidine were built and qualified for the prediction of metformin pharmacokinetics during drug-gene interaction, drug-drug interaction, and different stages of renal disease. The model files will be freely available in the Open Systems Pharmacology model repository. Current guidelines for metformin treatment of renally impaired patients should be reviewed to avoid overdosing in CKD3 and to allow metformin therapy of CKD4 patients.

中文翻译：

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二甲双胍和西咪替丁在健康成人和肾受损个体中的基于全身生理的综合药代动力学药物-药物-基因相互作用模型。

背景二甲双胍是广泛规定的抗糖尿病BCS III类药物（低渗透性），其吸收和处置依赖于主动转运。它被美国食品和药物管理局推荐作为有机阳离子转运蛋白 2/多药和毒素挤出蛋白的临床底物，用于药物-药物相互作用研究。西咪替丁是一种有效的有机阳离子转运蛋白 2/多药和毒素挤出蛋白抑制剂。目的 本研究的目的是提供基于机械全身生理学的二甲双胍和西咪替丁药代动力学模型，建立并评估以描述二甲双胍-SLC22A2 808G>T 药物-基因相互作用、西咪替丁-二甲双胍药物-药物相互作用以及肾功能损害对二甲双胍暴露的影响。方法 在 PK-Sim®（8.0 版）中开发了基于生理学的药代动力学模型。三十九项临床研究（剂量范围 0.001-2550 毫克），提供二甲双胍血浆和尿液数据、组织浓度的正电子发射断层扫描测量、有机阳离子转运蛋白 2 多态性志愿者的研究、与西咪替丁的药物相互作用研究以及来自患者的数据在慢性肾病的不同阶段，分别用于开发二甲双胍模型。27 项临床研究（剂量范围 100-800 mg）报告了西咪替丁血浆和尿液浓度，用于西咪替丁模型开发。结果 建立的基于生理的药代动力学模型充分描述了可用的临床数据，包括研究的药物-基因相互作用、药物-药物相互作用、和药物-药物-基因相互作用研究，以及肾功能不全期间的二甲双胍暴露。曲线下所有建模的药物-药物相互作用面积和最大浓度比都在观察到的比值的 1.5 倍以内。肾功能不全患者的临床数据显示，随着肾功能下降，二甲双胍暴露预期会增加，但也表明严重肾病的反调节机制；这些机制已根据临床前物种的发现实施到模型中。结论建立了基于全身生理学的二甲双胍和西咪替丁药代动力学模型，可用于预测药物-基因相互作用、药物-药物相互作用和肾脏疾病不同阶段的二甲双胍药代动力学。模型文件将在开放系统药理学模型库中免费提供。应审查目前肾功能不全患者二甲双胍治疗指南，以避免 CKD3 患者用药过量，并允许二甲双胍治疗 CKD4 患者。