International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment

Blinova, K. et al. (2018) International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell Reports, 24(13), pp. 3582-3592. (doi: 10.1016/j.celrep.2018.08.079) (PMID:30257217) (PMCID:PMC6226030)

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.

• Item Type: Articles
• Additional Information: The study was partly funded through a Food and Drug Administration Broad Agency Announcement (BAA) contract (FDABAA-15-00121) to the Health and Environmental Sciences Institute (HESI). This project has been funded in part with federal funds from the National Cancer Institute, NIH (contract HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services or the Food and Drug Administration, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. In addition, the study was partly funded through the Research on Regulatory Science of Pharmaceuticals and Medical Devices of the Japan Agency for Medical Research and Development (JP17mk0104027).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Godfrey
• Authors: Blinova, K., Dang, Q., Millard, D., Smith, G., Pierson, J., Guo, L., Brock, M., Lu, H. R., Kraushaar, U., Zeng, H., Shi, H., Zhang, X., Sawada, K., Osada, T., Kanda, Y., Sekino, Y., Pang, L., Feaster, T. K., Kettenhofen, R., Stockbridge, N., Strauss, D. G., and Gintant, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Cell Reports
• Publisher: Elsevier
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• First Published: First published in Cell Reports 24(13): 3582-3592
• Publisher Policy: Reproduced under a Creative Commons license