DATE: January 14, 2020
TIME: 8:00 am PST, 4:00 pm GMT, 5:00 pm CET
Drug-induced QT interval prolongation and Torsades de Pointes (TdP) arrhythmias are the leading causes for drug withdrawals from market and compound attrition during drug development. To assess potential cardiotoxicity of compounds, Comprehensive in vitro Proarrhythmia Assay (CiPA) is the new cardiac safety testing paradigm that includes in vitro assays using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). To adopt this paradigm, we developed a high-throughput hiPSC-CM assay using calcium-sensitive dyes that exhibit fast kinetic fluorescence detected by the high-speed fluorescence imaging platform, the FLIPR® Penta High-Throughput Cellular Screening System.
In this webinar, we will show data on evaluated concentration-dependent responses of 28 pharmacological agents linked to low, intermediate, and high TdP risk categories. Compound-induced proarrhythmic effects such as changes in beating rate and durations of these 28 agents were quantified and reported by monitoring changes in intracellular Ca2+ oscillations. Characterization of calcium oscillations allowed us to evaluate complex waveforms and events. In addition to changes in peak frequency and amplitude, we observed compound-induced proarrhythmic effects, peak prolongations, as well as increased complexity of patterns and appearance of secondary peaks at concentrations that correlated to clinically-relevant concentrations of QT prolongation and TdP arrhythmias. We characterized waveform irregularities using ScreenWorks® Peak Pro 2 software to obtain more than 20 dose-dependent readouts. Moreover, we assessed cellular and mitochondrial toxicity of these 28 compounds in the follow-up assay using the ImageXpress® Micro Confocal High-Content Imaging System to simultaneously monitor acute & chronic dosing effects of structural cardiotoxicity with multiple toxicity indicators. Taken together, we demonstrate that our high-throughput assay can provide an in vitro drug-induced proarrhythmia assessment as part of the cardiac safety paradigm encouraged by the CiPA initiative, and strengthens pharmacological safety profiles of drug candidates.
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LabRoots is approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E. ® Program. By attending this webinar, you can earn 1 Continuing Education credit once you have viewed the webinar in its entirety.