Christophe Bernard
Scaptest, Grand Rosière Hottomont, Belgium.
Toxicol Appl Pharmacol. 2025 Sep;502:117426. doi: 10.1016/j.taap.2025.117426. Epub 2025 Jun 7.
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.
在心脏安全药理学决策过程中，准确评估新药候选物的促心律失常风险对于预防严重副作用（如尖端扭转型室速（TdP），可能导致猝死）至关重要。综合体外促心律失常试验（CiPA）计划部分基于对人心室心肌细胞动作电位（AP）的计算机重建，旨在实现这一目标。由于基于大量人体数据，奥哈拉 - 鲁迪动态模型是CiPA计划批准的首个用于AP建模的算法。该算法被用于建立一个新数据库（www.scaptest.com用于心脏安全动作电位测试），以便根据诱导对AP形状和时程（静息膜电位、AP最大幅度、AP持续时间）产生影响所需的浓度，以及从该AP推断出的各种预测性安全参数（三角测量、复极跨壁离散度、反向使用依赖性、诱发早期后除极（EAD）的可能性、EAD的发生、导致EAD的阈值），全面描述一组200种化合物的计算机心脏安全概况。这种计算机心脏安全概况的描述有助于警示至少在高浓度下使用某些可能引发心脏安全问题（如TdP或兴奋性丧失）的化合物。
