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

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.