Posts by bchristophe

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

Occurrence of early afterdepolarization under healthy or hypertrophic cardiomyopathy conditions in the human ventricular endocardial myocyte: in silico study using 109 torsadogenic or non-torsadogenic compounds 

Toxicology and Applied Pharmacology, 438: 115914

https://www.sciencedirect.com/science/article/abs/pii/S0041008X2200059X   PMID: 35150662

read and download for free from the following link provided by Elsevier until April 05, 2022: https://authors.elsevier.com/a/1eb1w_,5zwpSdx

The goal of the CiPA initiative (Comprehensive in vitro Proarrhythmia Assay) was to assess a more accurate prediction of new drug candidate proarrhythmic severe liabilities such as torsades de pointes, for example. This new CiPA paradigm was partly based on in silico reconstruction of human ventricular cardiomyocyte action potential useful to identify repolarization abnormalities such early afterdepolarization (EAD), for example. Using the ToR-ORd algorithm (Tomek-Rodriguez-O'Hara-Rudy dynamic model), the aim of the present work was (i) to identify intracellular parameters leading to EAD occurrence under healthy and hypertrophic cardiomyopathy (HCM) conditions and (ii) to evaluate the prediction accuracy of compound torsadogenic risk based on EAD occurrence using a large set of 109 torsadogenic and non-torsadogenic compounds under both experimental conditions. In silico results highlighted the crucial involvement of Ca++ handling in the ventricular cardiomyocyte intracellular subspace compartment for the initiation of EAD, demonstrated by a higher amplitude of Ca++ release from junctional sarcoplasmic reticulum to subspace compartments (Jrel) measured at EAD take-off voltage in the presence vs. the absence of EAD initiated either by high IKr inhibition or by high enough concentration of a torsadogenic compound under both experimental conditions. Under healthy or HCM conditions, the prediction accuracy of the torsadogenic risk of compound based on EAD occurrence was observed to be 61 or 92%, respectively. This high accuracy under HCM conditions was discussed regarding its usefulness for cardiac safety pharmacology at least at early drug screening/preclinical stage of the drug development process.

https://doi.org/10.1016/j.taap.2022.115914

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 …