Comparison of in silico predictions of action potential duration in response to inhibition of I Kr and I CaL with new human ex vivo recordings

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 (I Kr ) can prolong the action potential duration (APD) and thereby the QT interval, and so are routinely rejected. However, simultaneous inhibition of the L-type Ca 2+ current (I CaL ) can mitigate the effect of I Kr inhibition, 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 I Kr and I CaL 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 I Kr and/or I CaL inhibition by applying 9 compounds at different concentrations to adult human ventricular trabeculae at physiological temperature. Compounds with similar effects on I Kr and I CaL exhibited less APD prolongation compared to selective I Kr inhibitors. We then integrated in vitro IC 50 patch-clamp data for I Kr and I CaL 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 I Kr and/or I CaL inhibition: they matched the data either for selective I Kr inhibitors or for compounds with comparable effects on I Kr and I CaL . This work introduces a new benchmarking framework to assess the predictivity of current and future AP models for APD response to I Kr and/or I CaL inhibition. This is an essential primary step towards an in silico framework that integrates in vitro data for translational clinical cardiac safety. Author summary Before an investigational drug reaches patients, it is tested in vitro to ensure it does not disrupt the heart’s electric activity. This testing often focuses on the drug’s ability to block a specific current called I Kr , 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, I CaL , along with I Kr , affects APD. We found that adding I CaL inhibition may mitigate the proarrhythmic effects caused by I Kr 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.