期刊
CELL REPORTS
卷 24, 期 13, 页码 3582-3592出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.08.079
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资金
- Food and Drug Administration Broad Agency Announcement (BAA) [FDABAA-15-00121]
- National Cancer Institute, NIH [HHSN261200800001E]
- Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute
- Research on Regulatory Science of Pharmaceuticals and Medical Devices of the Japan Agency for Medical Research and Development [JP17mk0104027]
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 similar to 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.
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