Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings

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. Author summaryBefore an investigational drug reaches patients, it is tested in vitro to ensure it does not disrupt the hearts electric activity. This testing often focuses on the drugs ability to block a specific current called IKr, which, if inhibited, can prolong the heart cells action potential duration (APD), which is associated with an increased risk of irregular heartbeats (proarrhythmia). Our study examines how blocking another current, ICaL, along with IKr, affects APD. We found that adding ICaL inhibition may mitigate the proarrhythmic effects caused by IKr inhibition alone. Understanding this balance can improve how we assess the cardiac safety of new drugs, potentially saving promising compounds from being incorrectly discarded. Currently, mathematical models help predict such cardiac responses, but no existing model accurately predicted our findings. Our new data could aid in developing more predictive models in the future. This will contribute to safer drug development and more effective treatments.