title: Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays.
abstract: Human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) are a potential source to develop assays for predictive electrophysiological safety screening. Published studies show that the relevant physiology and pharmacology exist but does not show the translation between stem cell cardiomyocyte assays and other preclinical safety screening assays, which is crucial for drug discovery and safety scientists and the regulators. Our studies are the first to show the pharmacology of ion channel blockade and compare them with existing functional cardiac electrophysiology studies. Ten compounds (a mixture of pure hERG [E-4031 and Cisapride], hERG and sodium [Flecainide, Mexiletine, Quinidine, and Terfenadine], calcium channel blockers [Nifedipine and Verapamil], and two proprietary compounds [GSK A and B]) were tested, and results from hiPSC-CMs studied on multielectrode arrays (MEA) were compared with other preclincial models and clinical drug concentrations and effects using integrated risk assessment plots. All ion channel blockers produced (1) functional effects on repolarization and depolarization around the IC25 and IC50 values and (2) excessive blockade of hERG and/or blockade of sodium current precipitated arrhythmias. Our MEA data show that hiPSC-CMs demonstrate relevant pharmacology and show excellent correlations to current functional cardiac electrophysiological studies. Based on these results, MEA assays using iPSC-CMs offer a reliable, cost effective, and surrogate to preclinical in vitro testing, in addition to the 3Rs (refine, reduce, and replace animals in research) benefit.
authors.affiliation: Safety Assessment, GlaxoSmithKline, Ware, Hertfordshire, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Harris
authors.forename: Mike
authors.initials: M
authors.lastname: Aylott
authors.forename: Yi
authors.initials: Y
authors.lastname: Cui
authors.forename: James B
authors.initials: JB
authors.lastname: Louttit
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: McMahon
authors.forename: Arun
authors.initials: A
authors.lastname: Sridhar
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers
keywords: cardiovascular safety; electrophysiology: ion channel blockers; hiPSC-CM; multielectrode array; preclinical.