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Christophe B. (2025)

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

Toxicology and applied pharmacology, 502, 117426

pdf file, PMID

A copy of this paper is available up to July 2025, 31 at the ELSEVIER share link : https://authors.elsevier.com/a/1lFM6,xhCDx0j

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.

The cardiac safety profiles of 3 new drugs (Ceritinib, Doxepin and Loperamide)  are now available (please sign in order to see the result)

The effects of the various compounds were tested on the cardiac action potential of the human cardiac endo-, mid- and epicardial myocyte using the ORd algorithm.

The compound in silico cardiac safety profile was based on search for:

Early afterdepolarization facilitation (EAD)

Transmural dispersion of repolarization increase or decrease (TDR)

 Reverse use dependence (RUD)

Triangulation increase or decrease

 Action potential duration prolongation or shortening (APD)

Maximal rate of AP rise increase or decrease  (Vmax)

 qnet  increase or decrease (iintegration sum of ICaL+IKr+IKs+INaL+Ito+IK1)

Vmin increase or decrease (minimal rate of AP decrease at the EAD take-off voltage)

The aim of the present database is to describe the in silico cardiac safety profile of drugs and their propensity to induce early afterdepolarization.  This is based on the study of the effects of drugs on the non-failing human ventricular myocyte action potential (endo-, mid- and epicardial subtypes) reconstructed by computational simulation (O’Hara-Rudy dynamic algorithm) in order to identify cardiac action potential abnormalities such as high variations and/or occurrence of resting membrane potential, action potential amplitude, maximal rate of action potential rise, action potential duration, triangulation, early afterdepolarization, transmural dispersion of repolarization, reverse use dependence, qNet or minimal rate of action potential decrease at early afterdepolarization take-off voltage. These various parameters are useful in order to assume a more accurate predictability of pro-arrhythmic liabilities of new drug candidate in the cardiac safety pharmacology screening process, which is the aim of the comprehensive in vitro pro-arrhythmia assay (CiPA) initiative. The in silico cardiac safety profile of each drug (150 drugs described in this first version) is illustrated by a separate page describing the effects induced by each compound on these various parameters. The results are summarized regarding the expected pro-arrhythmia profile of the various compounds as described by the CredibleMeds classification evaluating their propensity to induce torsade de pointes.

v1.0 : 150 drugs described   :    https://doi.org/10.5281/zenodo.7541554

pdf file (poorer graphic quality)  : www.scaptest.com/medias/files/scaptest-in-silico-cardiac-safety-profile-of-drugs-compresse1.pdf

Crumb W.J. Jr  & Christophe B.  (2020)

A risk profile of fenspiride using ion channel data and in silico action potential modeling

Journal of pharmacological and toxicological methods, 105, 106793

https://doi.org/10.1016/j.vascn.2020.106793

Safety Pharmacological Society / Barcelone / September 23-26, 2019

Recently, the marketing authorization for fenspiride containing products has been suspended in the EU due to reports of QT prolongation and torsade de pointes. As indicated in the Public Assessment report for Fenspiride, a total of 5 cases of QT prolongation including 3 cases of torsade de pointes were reported since the marketing of fenspiride. Most of these cases were in patients which had known or suspected risk factors for QT prolongation or arrhythmias (eg congenital LQT) or in patients taking other QT prolonging drugs or doses of fenspiride well above therapeutic. The goal of the present study was to characterize the effects of fenspiride on 3 ion channels which are known to play an important role in QT prolongation: hERG, late Nav1. 5, and Cav1. 2. Evaluating drugs against these ion channels and modeling with in silico action potential models is part of the new CiPA paradigm. In addition, we wanted to …