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Evolution of strategies to improve preclinical cardiac safety testing

Nature Reviews Drug Discovery volume 15, pages 457–471 (2016)Cite this article

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Abstract

The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the Kv11.1 current (also known as the hERG current or IKr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials.

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Figure 1: Link between delayed repolarization and torsades de pointes proarrhythmia.
Figure 2: Ionic basis for ventricular repolarization and drug-induced proarrhythmia.
Figure 3: Role of delayed repolarization and multi-channel blockade in defining proarrhythmic risk.
Figure 4: Elements of the Comprehensive in vitro Proarrhythmia Assay.
Figure 5: Electrophysiological approaches for evaluating proarrhythmia with human stem cell-derived cardiomyocytes.

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Acknowledgements

The authors wish to thank N. Thomas for helpful discussions and insights regarding high-content screening approaches with human stem cell-derived cardiomyocytes and for reviewing the manuscript. The authors also acknowledge multiple discussions with numerous individuals regarding new in vitro approaches that led to the development of the Comprehensive in vitro Proarrhythmia Assay (CiPA) and J. Green and J. Sutherland for their support with in silico reconstructions. AbbVie participated in the review and approval of this article.

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Authors and Affiliations

  1. Department of Integrative Pharmacology, Integrated Science and Technology, AbbVie, Department ZR 13, Building AP9 01, 1 North Waukegan Road, North Chicago, 60064–6118, Illinois, USA

    Gary Gintant

  2. Stanford University, 719 Carolina Street, San Francisco, 94107, California, USA

    Philip T. Sager

  3. Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, 20993, Maryland, USA

    Norman Stockbridge

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Correspondence to Gary Gintant.

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Competing interests

P.T.S. is a cardiac safety consultant (a member of the Data Safety and Monitoring Board, a member of the cardiovascular end-point committee, a consultant or an advisory board member) to Chemo, Milestone Pharmaceuticals, Medtronic, Cellceutix, Halozyme, NeuroVia, Trevi, S. K. Science, Viamet, Shin Nippon Biomedical Laboratories (SNBL), Biomedical Systems, iCardiac, Dart, Cancer Prevention, AbbVie, Heart Metabolics, Acadia, MyoKardia, Biogen, Theravance, Charles River, Acesion, Vivus and NDA Partners. Finally, P.T.S. is also a member of the Board of Directors of Anthera, Inc. He has no financial stake in any of the technologies discussed in the manuscript.

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Gintant, G., Sager, P. & Stockbridge, N. Evolution of strategies to improve preclinical cardiac safety testing. Nat Rev Drug Discov 15, 457–471 (2016). https://doi.org/10.1038/nrd.2015.34

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