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2018 - Assessment of Drug Effects on Cardiomyocyte Function: Comprehensive In Vitro Proarrhythmia Assay (CiPA) Results

Icon CE   CardioExcyte 96 poster, SOT Meeting 2018  logo pdf   (1.8 MB)

Abstract:

The on-going comprehensive in vitro pro-arrhythmia assay (CiPA) initiative aims to improve drug safety testing and help more beneficial chemical entities reach the market. The project consists of three main parts, which include 1) electrophysiological investigation of drug effects on human ventricular ion channels, 2) characterization of the in-silico cardiosafety model predictions, 3) assessment of discrepancies and gaps in fully integrated biological systems (human induced pluripotent stem-cell derived cardiac myocytes (iPSC- CMs) and the human ECG). To assess and validate drug effects on hiPSC-CMs in a combined measurement of cardiac excitation and contraction, a subset of compounds which are part of the Phase II CiPA study were tested. A prospective comparison study using combined extracellular field potential (EFP) and impedance technology was conducted across 4 independent laboratories testing 12 reference compounds in 4 independent commercially available hiPSC-CMs. Our data demonstrates that hERG channel blockers, such as Sotalol and Dofetilide prolonged field potential duration (FPD) at low concentration and induced arrhythmia as measured by field potential (FP) recording and impedance (IMP) recordings at higher concentrations. The cross-cell comparison displayed different minimal effective concentrations regarding FPD prolongation and cessation of beating. On the contrary, Diltiazem, a calcium channel inhibitor, weakened cell contractile activity and shortened FPD. Multichannel inhibitors, such Quinidine increased FPD, weakened the contraction force and induced arrhythmia. Furthermore, validation on low risk proarrhythmia compounds such as Tamoxifen and intermediate risk compounds such as Droperidol will be presented. Comparison of the compound effects across the four different sites showed the consistent trend of the effect. Taken together, commercially available hiPSC-CMs in conjunction with combined measurements of ion channel activity and contractility is a reliable approach for risk assessment of proarrhythmic compounds.

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