The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk

Lei, Chon Lok; Whittaker, Dominic G.; Mirams, Gary R.

Abstract

Background and Purpose
Drug-induced reduction of the rapid delayed rectifier potassium current carried by the human Ether-à-go-go-Related Gene (hERG) channel is associated with increased risk of arrhythmias. Recent updates to drug safety regulatory guidelines attempt to capture each drug’s hERG binding mechanism by combining in vitro assays with in silico simulations. In this study, we investigate the impact on in silico proarrhythmic risk predictions due to uncertainty in the hERG binding mechanism and physiological hERG current model.

Experimental Approach
Possible pharmacological binding models were designed for the hERG channel to account for known and postulated small molecule binding mechanisms. After selecting a subset of plausible binding models for each compound through calibration to available voltage-clamp electrophysiology data, we assessed their effects, and the effects of different physiological models, on proarrhythmic risk predictions.

Key Results
For some compounds, multiple binding mechanisms can explain the same data produced under the safety testing guidelines, which results in different inferred binding rates. This can result in substantial uncertainty in the predicted torsade risk, which often spans more than one risk category. By comparison, we found that the effect of a different hERG physiological current model on risk classification was subtle.

Conclusion and Implications
The approach developed in this study assesses the impact of uncertainty in hERG binding mechanisms on predictions of drug-induced proarrhythmic risk. For some compounds, these results imply the need for additional binding data to decrease uncertainty in safety-critical applications.

Citation

Lei, C. L., Whittaker, D. G., & Mirams, G. R. (2024). The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk. British Journal of Pharmacology, 181(7), 987-1004. https://doi.org/10.1111/bph.16250

• Journal Article Type: Article
• Acceptance Date: Aug 28, 2023
• Online Publication Date: Nov 8, 2023
• Publication Date: 2024-04
• Deposit Date: Sep 22, 2023
• Publicly Available Date: Nov 9, 2024
• Journal: British Journal of Pharmacology
• Print ISSN: 0007-1188
• Electronic ISSN: 1476-5381
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 181
• Issue: 7
• Pages: 987-1004
• DOI: https://doi.org/10.1111/bph.16250
• Keywords: risk, CiPA, mathematical modelling, safety pharmacology, binding mechanism, proarrhythmic, torsade, hERG
• Public URL: https://nottingham-repository.worktribe.com/output/18529486
• Publisher URL: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.16250