Validating Cardiac Ion Channel assays on the IonFluxTM System for the CiPA Paradigm

Abstract
Drug-induced QT interval prolongation and Torsades de Pointes (TdP) arrhythmia are the leading causes for drug withdrawal from the market. For the past decade, in vitro hERG channel assays and in vivo QT measurements have been conducted as surrogates for proarrhythmic risk propensity according to ICH S7B and ICH E14 guidelines. This paradigm, although effective, suffered from lack of specificity and led to unnecessary compound attrition during drug development. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a new cardiac safety testing paradigm under development with the goal of addressing this limitation and improving the ability to predict a drug’s proarrhythmic liability. This new paradigm includes a panel of in vitro assays that integrates the effects of test compounds on several cardiac ion channels. In this study, HEK-hERG, HEK-hNav1.5 peak and HEK- hNav1.5 late cardiac ionic currents were validated on the microfluidic-based automated IonFluxTM HT patch clamp system, using HESI-sponsored High Throughput Screening (HTS) cardiac protocols and assay solutions with a set of 12 compounds from Phase 1 to assess the variability and reproducibility of HTS platforms/sites and for the calibration and validation of the in silico action potential (AP) model. The results demonstrate suitability of the IonFluxTM HT system for high throughput screening of drug effects on cardiac ionic currents, and provide data for in silico reconstructions in the CiPA paradigm for defining proarrhythmic risk. 

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