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Toxicol Sci. 2018 Aug 1;164(2):550-562. doi: 10.1093/toxsci/kfy110.

Cross-Site Reliability of Human Induced Pluripotent stem cell-derived Cardiomyocyte Based Safety Assays Using Microelectrode Arrays: Results from a Blinded CiPA Pilot Study.

Author information

1
Axion Biosystems Inc, Atlanta, Georgia 30309.
2
US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland 20993.
3
Bristol-Myers Squibb Company, Princeton, New Jersey 08543.
4
Acea Biosciences, San Diego, California 92121.
5
Cyprotex, Watertown, Massachusetts 01746.
6
Naturwissenschaftliches und Medizinisches Institut, Reutlingen, Germany.
7
Merck & Co., Inc., Safety & Exploratory Pharmacology Department, West Point, Pennsylvania.
8
Janssen, Beerse, Belgium.
9
Sanofi R&D Preclinical Safety, Paris, France.
10
Stanford University School of Medicine, Stanford Cardiovascular Institute, Stanford, California.
11
Ncardia, Leiden, The Netherlands.
12
Cellular Dynamics International a FujiFilm, Company, Madison, Wisconsin 53508.
13
Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Frederick, Maryland 21702.
14
ILSI-Health and Environmental Sciences Institute, Washington, District of Columbia 20009.
15
Integrative Pharmacology (Dept ZR13), Integrated Science and Technology. AbbVie, North Chicago, Illinois 60064.

Abstract

Recent in vitro cardiac safety studies demonstrate the ability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to detect electrophysiologic effects of drugs. However, variability contributed by unique approaches, procedures, cell lines, and reagents across laboratories makes comparisons of results difficult, leading to uncertainty about the role of hiPSC-CMs in defining proarrhythmic risk in drug discovery and regulatory submissions. A blinded pilot study was conducted to evaluate the electrophysiologic effects of 8 well-characterized drugs on 4 cardiomyocyte lines using a standardized protocol across 3 microelectrode array platforms (18 individual studies). Drugs were selected to define assay sensitivity of prominent repolarizing currents (E-4031 for IKr, JNJ303 for IKs) and depolarizing currents (nifedipine for ICaL, mexiletine for INa) as well as drugs affecting multichannel block (flecainide, moxifloxacin, quinidine, and ranolazine). Inclusion criteria for final analysis was based on demonstrated sensitivity to IKr block (20% prolongation with E-4031) and L-type calcium current block (20% shortening with nifedipine). Despite differences in baseline characteristics across cardiomyocyte lines, multiple sites, and instrument platforms, 10 of 18 studies demonstrated adequate sensitivity to IKr block with E-4031 and ICaL block with nifedipine for inclusion in the final analysis. Concentration-dependent effects on repolarization were observed with this qualified data set consistent with known ionic mechanisms of single and multichannel blocking drugs. hiPSC-CMs can detect repolarization effects elicited by single and multichannel blocking drugs after defining pharmacologic sensitivity to IKr and ICaL block, supporting further validation efforts using hiPSC-CMs for cardiac safety studies.

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