International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment
Ksenia Blinova,
Qianyu Dang,
Daniel Millard,
Godfrey Smith,
Jennifer Pierson,
Liang Guo,
Mathew Brock,
Hua Rong Lu,
Udo Kraushaar,
Haoyu Zeng,
Hong Shi,
Xiaoyu Zhang,
Kohei Sawada,
Tomoharu Osada,
Yasunari Kanda,
Yuko Sekino,
Li Pang,
Tromondae K. Feaster,
Ralf Kettenhofen,
Norman Stockbridge,
David G. Strauss,
Gary Gintant
Affiliations
Ksenia Blinova
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; Corresponding author
Qianyu Dang
Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA
Daniel Millard
Axion BioSystems, Atlanta, GA 30309, USA
Godfrey Smith
University of Glasgow, Glasgow G12 8QQ, Scotland, UK; Clyde Biosciences, Newhouse ML1 5UH, Scotland, UK
Jennifer Pierson
Health and Environmental Sciences Institute, Washington, DC 20005, USA
Liang Guo
Investigative Toxicology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA
NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
Haoyu Zeng
Merck, Safety & Exploratory Pharmacology Department, West Point, PA 19486, USA
Hong Shi
Bristol-Myers Squibb, New York, NY 10154, USA
Xiaoyu Zhang
ACEA Biosciences, San Diego, CA 92121, USA
Kohei Sawada
Eisai, Tsukuba, Ibaraki 300-2635, Japan; The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Tomoharu Osada
LSI Medience, Chiyoda-ku, Tokyo 101-8517, Japan
Yasunari Kanda
Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Kanagawa 210-9501, Japan
Yuko Sekino
The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Kanagawa 210-9501, Japan
Li Pang
Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA
Tromondae K. Feaster
Cellular Dynamics International–A FUJIFILM Company, Madison, WI 53711, USA
Ralf Kettenhofen
Ncardia, Cologne 50829, Germany
Norman Stockbridge
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
David G. Strauss
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
Gary Gintant
AbbVie, North Chicago, IL 60064-6118, USA; Corresponding author
Summary: 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. : Blinova et al. tested human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for improving torsades de pointes arrhythmia risk prediction of drugs in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative. This validation study confirms their utility based on electrophysiologic responses to 28 blinded drugs, with minimal influence from cell lines, test sites, and electrophysiological platforms. Keywords: comprehensive in vitro proarrhythmia assay, CiPA, human-induced pluripotent stem cell-derived cardiomycotes, hiPSC-CM, drug-induced ventricular arrhythmia Torsade de Pointes, microelectrode array, voltage-sensitive dyes
