{"id":17025,"date":"2025-03-17T11:08:11","date_gmt":"2025-03-17T11:08:11","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=17025"},"modified":"2025-03-17T11:08:11","modified_gmt":"2025-03-17T11:08:11","slug":"2025-comparison-of-in-silico-predictions-of-action-potential-duration-in-response-to-inhibition-of-ikr-and-ical-with-new-human-ex-vivo-recordings","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2025-comparison-of-in-silico-predictions-of-action-potential-duration-in-response-to-inhibition-of-ikr-and-ical-with-new-human-ex-vivo-recordings\/","title":{"rendered":"2025 &#8211; Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings"},"content":{"rendered":"<p>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<sup>+<\/sup>\u00a0current (I<sub>Kr<\/sub>) 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<sup>2+<\/sup>\u00a0current (I<sub>CaL<\/sub>) can mitigate the effect of I<sub>Kr<\/sub>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<sub>Kr<\/sub>\u00a0and I<sub>CaL<\/sub>\u00a0inhibition, 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\u00a0<em>ex vivo<\/em>\u00a0for APD response to I<sub>Kr<\/sub>\u00a0and\/or I<sub>CaL<\/sub>\u00a0inhibition by applying 9 compounds at different concentrations to adult human ventricular trabeculae at physiological temperature. Compounds with similar effects on I<sub>Kr<\/sub>\u00a0and I<sub>CaL<\/sub>\u00a0exhibited less APD prolongation compared to selective I<sub>Kr<\/sub>\u00a0inhibitors. We then integrated\u00a0<em>in vitro<\/em>\u00a0IC<sub>50<\/sub>\u00a0patch-clamp data for I<sub>Kr<\/sub>\u00a0and I<sub>CaL<\/sub>\u00a0inhibition by the tested compounds into simulations with AP models. Models were assessed against the\u00a0<em>ex vivo<\/em>\u00a0data 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<sub>Kr<\/sub>\u00a0and\/or I<sub>CaL<\/sub>\u00a0inhibition: they matched the data either for selective I<sub>Kr<\/sub>\u00a0inhibitors or for compounds with comparable effects on I<sub>Kr<\/sub>\u00a0and I<sub>CaL<\/sub>. This work introduces a new benchmarking framework to assess the predictivity of current and future AP models for APD response to I<sub>Kr<\/sub>\u00a0and\/or I<sub>CaL<\/sub>\u00a0inhibition. This is an essential primary step towards an\u00a0<em>in silico<\/em>\u00a0framework that integrates\u00a0<em>in vitro<\/em>\u00a0data for translational clinical cardiac safety.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[],"target_categories":[],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-17025","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-drug-discovery"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/17025","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=17025"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=17025"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=17025"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=17025"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=17025"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=17025"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=17025"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=17025"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=17025"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}