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International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment

  1. Author:
    Blinova, Ksenia
    Dang, Qianyu
    Millard, Daniel
    Smith, Godfrey
    Pierson, Jennifer
    Guo, Liang
    Brock, Mathew
    Lu, Hua Rong
    Kraushaar, Udo
    Zeng, Haoyu
    Shi, Hong
    Zhang, Xiaoyu
    Sawada, Kohei
    Osada, Tomoharu
    Kanda, Yasunari
    Sekino, Yuko
    Pang, Li
    Feaster, Tromondae K
    Kettenhofen, Ralf
    Stockbridge, Norman
    Strauss, David G
    Gintant, Gary

  2. Author Address

    Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: ksenia.blinova@fda.hhs.gov., Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA., Axion BioSystems, Atlanta, GA 30309, USA., University of Glasgow, Glasgow G12 8QQ, Scotland, UK; Clyde Biosciences, Newhouse ML1 5UH, Scotland, UK., Health and Environmental Sciences Institute, Washington, DC 20005, USA., Investigative Toxicology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA., Genentech, San Francisco, CA 94080, USA., Discovery Sciences, R&D, Janssen Pharmaceutical (JNJ), Beerse, Belgium., NMI Natural and Medical Sciences Institute at the University of T 252;bingen, Reutlingen, Germany., Merck, Safety & Exploratory Pharmacology Department, West Point, PA 19486, USA., Bristol-Myers Squibb, New York, NY 10154, USA., ACEA Biosciences, San Diego, CA 92121, USA., Eisai, Tsukuba, Ibaraki 300-2635, Japan; The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan., LSI Medience, Chiyoda-ku, Tokyo 101-8517, Japan., Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Kanagawa 210-9501, Japan., The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Kanagawa 210-9501, Japan., Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA., Cellular Dynamics International-A FUJIFILM Company, Madison, WI 53711, USA., Ncardia, Cologne 50829, Germany., Division of Cardiovascular and Renal Products, Office of Drug Evaluation I, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA., Division of Applied and Regulatory Science, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA., AbbVie, North Chicago, IL 60064-6118, USA. Electronic address: gary.gintant@abbvie.com.,
    1. Year: 2018
    2. Date: Sep 25
  2. Journal: Cell Reports
    1. 24
    2. 13
    3. Pages: 3582-3592
  4. Type of Article: Article
  5. ISSN: 2211-1247
  1. Abstract:

    To assess the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro proarrhythmia model, we evaluated the concentration dependence and sources of variability of electrophysiologic responses to 28 drugs linked to low, intermediate, and high torsades de pointes (TdP) risk categories using two commercial cell lines and standardized protocols in a blinded multisite study using multielectrode array or voltage-sensing optical approaches. Logistical and ordinal linear regression models were constructed using drug responses as predictors and TdP risk categories as outcomes. Three of seven predictors (drug-induced arrhythmia-like events and prolongation of repolarization at either maximum tested or maximal clinical exposures) categorized drugs with reasonable accuracy (area under the curve values of receiver operator curves ~0.8). hiPSC-CM line, test site, and platform had minimal influence on drug categorization. These results demonstrate the utility of hiPSC-CMs to detect drug-induced proarrhythmic effects as part of the evolving Comprehensive In Vitro Proarrhythmia Assay paradigm. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2018.08.079
  3. PMID: 30257217
  4. View record in Web of Science®
  5. WOS: 000445524700020
  6. PII : S2211-1247(18)31383-4

Library Notes

  1. Fiscal Year: FY2017-2018
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