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Toxicol Sci. 2017 Jan;155(1):234-247. doi: 10.1093/toxsci/kfw200. Epub 2016 Oct 3.

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.

Author information

1
US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland; ksenia.blinova@fda.hhs.gov.
2
US Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, Maryland.
3
US Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Silver Spring, Maryland.
4
BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
5
University of Glasgow, Glasgow, UK.
6
Clyde Biosciences, Glasgow, UK.
7
Zenas Technologies, Metairie, Louisiana.
8
Division of Biochemical Toxicology, US Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
9
Axion BioSystems, Atlanta, Georgia.
10
US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology, Silver Spring, Maryland.

Abstract

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.

KEYWORDS:

CiPA; Cor.4U.; MEA; VSD; iCell; iPSC-CM

PMID:
27701120
PMCID:
PMC6093617
DOI:
10.1093/toxsci/kfw200
[Indexed for MEDLINE]
Free PMC Article

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