Importance of modelling hERG binding in predicting drug-induced action potential prolongations for drug safety assessment

Farm, Hui Jia; Clerx, Michael; Cooper, Fergus; Polonchuk, Liudmila; Wang, Ken; Gavaghan, David J.; Lei, Chon Lok

doi:10.3389/fphar.2023.1110555

Importance of modelling hERG binding in predicting drug-induced action potential prolongations for drug safety assessment

Farm, Hui Jia; Clerx, Michael; Cooper, Fergus; Polonchuk, Liudmila; Wang, Ken; Gavaghan, David J.; Lei, Chon Lok

Authors

Hui Jia Farm

MICHAEL CLERX MICHAEL.CLERX@NOTTINGHAM.AC.UK
Senior Research Fellow

Fergus Cooper

Liudmila Polonchuk

Ken Wang

David J. Gavaghan

Chon Lok Lei

Abstract

Reduction of the rapid delayed rectifier potassium current (IKr) via drug binding to the human Ether-à-go-go-Related Gene (hERG) channel is a well recognised mechanism that can contribute to an increased risk of Torsades de Pointes. Mathematical models have been created to replicate the effects of channel blockers, such as reducing the ionic conductance of the channel. Here, we study the impact of including state-dependent drug binding in a mathematical model of hERG when translating hERG inhibition to action potential changes. We show that the difference in action potential predictions when modelling drug binding of hERG using a state-dependent model versus a conductance scaling model depends not only on the properties of the drug and whether the experiment achieves steady state, but also on the experimental protocols. Furthermore, through exploring the model parameter space, we demonstrate that the state-dependent model and the conductance scaling model generally predict different action potential prolongations and are not interchangeable, while at high binding and unbinding rates, the conductance scaling model tends to predict shorter action potential prolongations. Finally, we observe that the difference in simulated action potentials between the models is determined by the binding and unbinding rate, rather than the trapping mechanism. This study demonstrates the importance of modelling drug binding and highlights the need for improved understanding of drug trapping which can have implications for the uses in drug safety assessment.

Citation

Farm, H. J., Clerx, M., Cooper, F., Polonchuk, L., Wang, K., Gavaghan, D. J., & Lei, C. L. (2023). Importance of modelling hERG binding in predicting drug-induced action potential prolongations for drug safety assessment. Frontiers in Pharmacology, 14, Article 1110555. https://doi.org/10.3389/fphar.2023.1110555

Journal Article Type	Article
Acceptance Date	Feb 22, 2023
Online Publication Date	Mar 20, 2023
Publication Date	Mar 20, 2023
Deposit Date	May 8, 2023
Publicly Available Date	May 9, 2023
Journal	Frontiers in Pharmacology
Electronic ISSN	1663-9812
Publisher	Frontiers Media SA
Peer Reviewed	Peer Reviewed
Volume	14
Article Number	1110555
DOI	https://doi.org/10.3389/fphar.2023.1110555
Keywords	Pharmacology, drug binding, drug trapping, IC50 (50% inhibition concentration), mathematical modelling, hERG channel, action potential predictions
Public URL	https://nottingham-repository.worktribe.com/output/19286539
Publisher URL	https://www.frontiersin.org/articles/10.3389/fphar.2023.1110555/full
Additional Information	© 2023 Farm, Clerx, Cooper, Polonchuk, Wang, Gavaghan and Lei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.