Simulation of multiple ion channel block provides improved prediction of compounds’ clinical torsadogenic risk

Mirams, Gary R.; Cui, Yi; Sher, Anna; Fink, Martin; Cooper, Jonathan; Heath, Bronagh M.; McMahon, Nick C.; Gavaghan, David J.; Noble, Denis

Abstract

© 2011 The Author. Aims The level of inhibition of the human Ether - go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50 (IC50) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.Methods and resultsWe collected multiple ion channel data (hERG, Na, l-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC50 values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.ConclusionThe suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.

Citation

Mirams, G. R., Cui, Y., Sher, A., Fink, M., Cooper, J., Heath, B. M., …Noble, D. (2011). Simulation of multiple ion channel block provides improved prediction of compounds’ clinical torsadogenic risk. Cardiovascular Research, 91(1), 53-61. https://doi.org/10.1093/cvr/cvr044

• Journal Article Type: Article
• Acceptance Date: Feb 3, 2011
• Online Publication Date: Feb 7, 2011
• Publication Date: Jul 1, 2011
• Deposit Date: Jan 14, 2020
• Journal: Cardiovascular Research
• Print ISSN: 0008-6363
• Electronic ISSN: 1755-3245
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 91
• Issue: 1
• Pages: 53-61
• DOI: https://doi.org/10.1093/cvr/cvr044
• Public URL: https://nottingham-repository.worktribe.com/output/3217693
• Publisher URL: https://academic.oup.com/cardiovascres/article/91/1/53/333710