International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment
Year: 2018
Type: article
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.
Source: Cell Reports
Authors: 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
Institutions: United States Food and Drug Administration, Center for Devices and Radiological Health, Center for Drug Evaluation and Research, Axion Biosystems (United States), University of Glasgow, Health and Environmental Sciences Institute, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. (United States), Genentech, Janssen (Belgium), Natural and Medical Sciences Institute, University of Tübingen, Merck & Co., Inc., Rahway, NJ, USA (United States), Bristol-Myers Squibb (United States), ACEA Biosciences (United States), Eisai (Japan), The University of Tokyo, LSI Medience Corporation (Japan), National Institute of Health Sciences, National Center for Toxicological Research, Cellular Dynamics International (United States), AbbVie (United States)
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: U.S. Department of Health and Human Services, Bristol-Myers Squibb, Health and Environmental Sciences Institute, Japan Agency for Medical Research and Development, National Measurement Institute, ACEA Biosciences, Eisai, National Institutes of Health, U.S. Food and Drug Administration, National Cancer Institute
OpenAlex ID: W2893420171