In silico cardiac safety profile of drugs and their potential to induce clinical cardiotoxicity

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-06-07 DOI:10.1016/j.taap.2025.117426

Bernard Christophe

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引用次数: 0

Abstract

During the cardiac safety pharmacology decision-making process, a precise evaluation of the proarrhythmic liabilities of new drug candidates is essential to prevent serious side effects like torsade de pointes (TdP), which could result in sudden death. Based in part on in silico reconstruction of the human ventricular cardiomyocyte action potential (AP), the Comprehensive in vitro Proarrhthymia Assay (CiPA) initiative aims to achieve this goal. Because it is based on a significant amount of human data, the O'Hara-Rudy dynamic model is the first algorithm approved by the CiPA initiative for AP modeling. This algorithm was used to build a new database (www.scaptest.com for Safe Cardiac Action Potential test) in order to fully describe the in silico cardiac safety profile of a very large set of 200 compounds based on their concentration required to induce effects on AP shape and time course (resting membrane potential, AP maximal amplitude, AP duration) as well as on various predictive safety parameters extrapolated from this AP (triangulation, transmural dispersion of repolarization, reverse use dependence, likelihood of inducing early afterdepolarization (EAD), occurrence of EAD, threshold leading to EAD). This description of the in silico cardiac safety profile helps warn against the use of certain compounds possibly inducing cardiac safety issues (such as TdP or inexcitability) at least at high concentrations.

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药物的心脏安全性及其诱发临床心脏毒性的潜力

在心脏安全药理学决策过程中，准确评估候选新药的促心律失常副作用对于预防可能导致猝死的严重副作用至关重要，如点扭转（TdP）。部分基于人心室心肌细胞动作电位（AP）的计算机重建，综合体外心律失常检测（CiPA）计划旨在实现这一目标。由于O'Hara-Rudy动态模型基于大量的人类数据，因此它是CiPA倡议批准的第一个用于AP建模的算法。该算法被用于建立一个新的数据库（www.scaptest.com for Safe Cardiac Action Potential test），以便根据对AP形状和时间过程（静息膜电位、AP最大振幅、AP持续时间）的影响所需的浓度，以及从AP推断出的各种预测安全性参数(三角测量、跨壁复极化弥散、反向使用依赖，诱发早期后去极化（EAD）的可能性，EAD的发生，导致EAD的阈值)。这种对计算机心脏安全概况的描述有助于警告使用某些至少在高浓度下可能引起心脏安全问题（如TdP或不可兴奋性）的化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.