Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative

Li, Zhihua; Wu, Wendy W.; Sheng, Jiansong; Tran, Phu N.; Wu, Min; Ranolph, Aaron; Johnstone, Ross H.; Mirams, Gary R.; Kuryshev, Yuri; Kramer, James; Wu, Caiyun; Crumb, William J.; Strauss, David G.

Abstract

International Council on Harmonization S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are proarrhythmic. In response, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) was proposed that integrates multi-ion channel pharmacology data in vitro into a human cardiomyocyte model in silico for proarrhythmia risk assessment. Previously, we reported the model optimization and proarrhythmia metric selection based on CiPA training drugs. In this study, we report the application of the prespecified model and metric to independent CiPA validation drugs. Over two validation datasets, the CiPA model performance meets all pre-specified measures for ranking and classifying validation drugs, and outperforms alternatives, despite some in vitro data differences between the two datasets due to different experimental conditions and quality control procedures This suggests that the current CiPA model/metric is fit for regulatory use, and standard experimental protocols and quality control criteria could increase the model prediction accuracy even further.

Citation

Li, Z., Wu, W. W., Sheng, J., Tran, P. N., Wu, M., Ranolph, A., Johnstone, R. H., Mirams, G. R., Kuryshev, Y., Kramer, J., Wu, C., Crumb, W. J., & Strauss, D. G. (2019). Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative. Clinical Pharmacology and Therapeutics, 105(2), 466-475. https://doi.org/10.1002/cpt.1184

• Journal Article Type: Article
• Acceptance Date: Jul 25, 2018
• Online Publication Date: Aug 27, 2018
• Publication Date: 2019-02
• Deposit Date: Jul 31, 2018
• Publicly Available Date: Sep 11, 2018
• Journal: Clinical Pharmacology & Therapeutics
• Print ISSN: 0009-9236
• Electronic ISSN: 1532-6535
• Publisher: American Society for Clinical Pharmacology and Therapeutics
• Peer Reviewed: Peer Reviewed
• Volume: 105
• Issue: 2
• Pages: 466-475
• DOI: https://doi.org/10.1002/cpt.1184
• Public URL: https://nottingham-repository.worktribe.com/output/947750
• Publisher URL: https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1184?af=R
• Contract Date: Sep 11, 2018