A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

Author:

Fermini Bernard1,Hancox Jules C.2,Abi-Gerges Najah34,Bridgland-Taylor Matthew5,Chaudhary Khuram W.6,Colatsky Thomas7,Correll Krystle8,Crumb William9,Damiano Bruce10,Erdemli Gul11,Gintant Gary12,Imredy John13,Koerner John14,Kramer James15,Levesque Paul16,Li Zhihua7,Lindqvist Anders17,Obejero-Paz Carlos A.15,Rampe David18,Sawada Kohei19,Strauss David G.20,Vandenberg Jamie I.21

Affiliation:

1. Global Safety Pharmacology, Pfizer Inc., Groton, CT, USA

2. School of Physiology and Pharmacology, University of Bristol, Bristol, UK

3. Translational Safety, Drug Safety and Metabolism, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield, UK

4. AnaBios Corporation, San Diego, CA, USA

5. Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield, UK

6. Safety Assessment, GlaxoSmithKline, King of Prussia, PA, USA

7. Division of Applied Regulatory Science, CDER, US Food and Drug Administration, Silver Spring, MD, USA

8. Safety Pharmacology Society, Reston, VA, USA

9. Zenas Technologies LLC, New Orleans, LA, USA

10. Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development LLC, Spring House, PA, USA

11. Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA

12. Department of Integrative Pharmacology, Integrated Sciences & Technology, AbbVie, North Chicago, IL, USA

13. Department of Safety Assessment, Merck & Co, Kenilworth, NJ, USA

14. Division of Cardiovascular and Renal Products, CDER, U.S. Food and Drug Administration, Silver Spring, MD, USA

15. ChanTest, A Charles River Company, Cleveland, OH, USA

16. Bristol Myers Squibb Research & Development, Princeton, NJ, USA

17. Biolin Scientific, Ballerup, DK

18. Preclinical Safety, Sanofi, Bridgewater, NJ, USA

19. Global Cardiovascular Assessment, Eisai Co., Ltd., Ibaraki, Japan

20. Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD, USA

21. Victor Chang Cardiac Research Institute, St Vincent’s Clinical School, University of NSW, Darlinghurst, NSW, Australia

Abstract

For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when considering costly thorough QT (TQT) studies conducted later in drug development. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is a public-private collaboration with the aim of updating the existing cardiac safety testing paradigm to better evaluate arrhythmia risk and remove the need for TQT studies. It is hoped that CiPA will produce a standardized ion channel assay approach, incorporating defined tests against major cardiac ion channels, the results of which then inform evaluation of proarrhythmic actions in silico, using human ventricular action potential reconstructions. Results are then to be confirmed using human (stem cell–derived) cardiomyocytes. This perspective article reviews the rationale, progress of, and challenges for the CiPA initiative, if this new paradigm is to replace existing practice and, in time, lead to improved and widely accepted cardiac safety testing guidelines.

Publisher

Elsevier BV

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