Comparison of in silico predictions of action potential duration in response to inhibition of IKrand ICaLwith new human ex vivo recordings

Barral, Yann-Stanislas H.M.; Polonchuk, Liudmila; Clerx, Michael; Gavaghan, David J.; Mirams, Gary R.; Wang, Ken

Abstract

During drug development, candidate compounds are extensively tested for proar-rhythmic risk and in particular risk of Torsade de Pointes (TdP), as indicated by prolongation of the QT interval. Drugs that inhibit the rapid delayed rectifier K+ current (IKr) can prolong the action potential duration (APD) and thereby the QT interval, and so are routinely rejected. However, simultaneous inhibition of the L-type Ca2+ current (ICaL) can mitigate the effect of IKrinhibition, so that including both effects can improve test specificity. Mathematical models of the action potential (AP) can be used to predict the APD prolongation resulting from a given level of IKr and ICaL inhibition, but for use in safety-testing their predictive capabilities should first be carefully verified. We present the first systematic comparison between experimental drug-induced APD and predictions by AP models. New experimental data were obtained ex vivo for APD response to IKr and/or ICaL inhibition by applying 9 compounds at different concentrations to adult human ventricular trabeculae at physiological temperature. Compounds with similar effects on IKr and ICaL exhibited less APD prolongation compared to selective IKr inhibitors. We then integrated in vitro IC50 patch-clamp data for IKr and ICaL inhibition by the tested compounds into simulations with AP models. Models were assessed against the ex vivo data on their ability to recapitulate drug-induced APD changes observed experimentally. None of the tested AP models reproduced the APD changes observed experimentally across all combinations and degrees of IKr and/or ICaL inhibition: they matched the data either for selective IKr inhibitors or for compounds with comparable effects on IKr and ICaL. This work introduces a new benchmarking framework to assess the predictivity of current and future AP models for APD response to IKr and/or ICaL inhibition. This is an essential primary step towards an in silico framework that integrates in vitro data for translational clinical cardiac safety.

Citation

Barral, Y.-S. H., Polonchuk, L., Clerx, M., Gavaghan, D. J., Mirams, G. R., & Wang, K. Comparison of in silico predictions of action potential duration in response to inhibition of IKrand ICaLwith new human ex vivo recordings

• Working Paper Type: Preprint
• Deposit Date: Mar 11, 2025
• Publicly Available Date: Mar 11, 2025
• DOI: https://doi.org/10.1101/2025.02.26.640287
• Public URL: https://nottingham-repository.worktribe.com/output/46313043