Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept

IF 2.8 4区医学 Q2 TOXICOLOGY Toxicology Mechanisms and Methods Pub Date : 2017-02-01 DOI:10.1080/15376516.2016.1256460

Mitra Abbasi, B. Small, N. Patel, M. Jamei, S. Polak

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引用次数: 16

Abstract

Abstract Background and purpose: To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. Experimental approach: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. Results: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). Conclusion and implications: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.

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使用体外数据和基于单细胞的计算机模型对药物致心律失常风险的早期评估：概念验证

摘要背景和目的：使用药物特异性临床前心脏电生理学数据来确定计算机模型的预测性能，以研究虚拟人受试者中药物诱导的心律失常风险（如尖端扭转（TdP））。实验方法：为了评估药物致心律失常的风险，我们使用了一组描述所研究药物引发的离子通道抑制的体外电生理测量。心脏安全模拟器2.0版（CSS；Simcyp，Sheffield，UK）平台用于模拟人类左心室心肌细胞动作电位模型。结果：本研究利用现有的实验数据显示了药物浓度变化对特定离子电流的影响。模拟结果根据药物浓度阈值和log（阈值浓度/有效治疗血浆浓度（ETPC））显示安全阈值。结论和意义：我们再现了心脏细胞的潜在生物物理特征，导致了与心律失常相关的药物的影响（动作电位持续时间（APD）、QT延长和TdP），这些药物在已发表的3D模拟中观察到，但计算负担要小得多。

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来源期刊

Toxicology Mechanisms and Methods TOXICOLOGY-

自引率

3.10%

发文量

期刊介绍： Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.