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

Bernard Fermini¹, Jules C Hancox², Najah Abi-Gerges³, Matthew Bridgland-Taylor⁴, Khuram W Chaudhary⁵, Thomas Colatsky⁶, Krystle Correll⁷, William Crumb⁸, Bruce Damiano⁹, Gul Erdemli¹⁰, Gary Gintant¹¹, John Imredy¹², John Koerner¹³, James Kramer¹⁴, Paul Levesque¹⁵, Zhihua Li⁶, Anders Lindqvist¹⁶, Carlos A Obejero-Paz¹⁴, David Rampe¹⁷, Kohei Sawada¹⁸, David G Strauss¹⁹, Jamie I Vandenberg²⁰

Affiliations

¹ Global Safety Pharmacology, Pfizer Inc., Groton, CT, USA Bernard.fermini@pfizer.com.
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 AnaBios Corporation, San Diego, CA, USA.
⁴ Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield, UK.
⁵ Safety Assessment, GlaxoSmithKline, King of Prussia, PA, USA.
⁶ Division of Applied Regulatory Science, CDER, US Food and Drug Administration, Silver Spring, MD, USA.
⁷ Safety Pharmacology Society, Reston, VA, USA.
⁸ Zenas Technologies LLC, New Orleans, LA, USA.
⁹ Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development LLC, Spring House, PA, USA.
¹⁰ Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA.
¹¹ Department of Integrative Pharmacology, Integrated Sciences & Technology, AbbVie, North Chicago, IL, USA.
¹² Department of Safety Assessment, Merck & Co, Kenilworth, NJ, USA.
¹³ Division of Cardiovascular and Renal Products, CDER, U.S. Food and Drug Administration, Silver Spring, MD, USA.
¹⁴ ChanTest, A Charles River Company, Cleveland, OH, USA.
¹⁵ Bristol Myers Squibb Research & Development, Princeton, NJ, USA.
¹⁶ Biolin Scientific, Ballerup, DK.
¹⁷ Preclinical Safety, Sanofi, Bridgewater, NJ, USA.
¹⁸ Global Cardiovascular Assessment, Eisai Co., Ltd., Ibaraki, Japan.
¹⁹ Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD, USA.
²⁰ Victor Chang Cardiac Research Institute, St Vincent's Clinical School, University of NSW, Darlinghurst, NSW, Australia.

PMID: 26170255
DOI: 10.1177/1087057115594589

Review

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

Bernard Fermini et al. J Biomol Screen. 2016 Jan.

. 2016 Jan;21(1):1-11.

doi: 10.1177/1087057115594589. Epub 2015 Jul 13.

Authors

Affiliations

¹ Global Safety Pharmacology, Pfizer Inc., Groton, CT, USA Bernard.fermini@pfizer.com.
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 AnaBios Corporation, San Diego, CA, USA.
⁴ Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Macclesfield, UK.
⁵ Safety Assessment, GlaxoSmithKline, King of Prussia, PA, USA.
⁶ Division of Applied Regulatory Science, CDER, US Food and Drug Administration, Silver Spring, MD, USA.
⁷ Safety Pharmacology Society, Reston, VA, USA.
⁸ Zenas Technologies LLC, New Orleans, LA, USA.
⁹ Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development LLC, Spring House, PA, USA.
¹⁰ Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA.
¹¹ Department of Integrative Pharmacology, Integrated Sciences & Technology, AbbVie, North Chicago, IL, USA.
¹² Department of Safety Assessment, Merck & Co, Kenilworth, NJ, USA.
¹³ Division of Cardiovascular and Renal Products, CDER, U.S. Food and Drug Administration, Silver Spring, MD, USA.
¹⁴ ChanTest, A Charles River Company, Cleveland, OH, USA.
¹⁵ Bristol Myers Squibb Research & Development, Princeton, NJ, USA.
¹⁶ Biolin Scientific, Ballerup, DK.
¹⁷ Preclinical Safety, Sanofi, Bridgewater, NJ, USA.
¹⁸ Global Cardiovascular Assessment, Eisai Co., Ltd., Ibaraki, Japan.
¹⁹ Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD, USA.
²⁰ Victor Chang Cardiac Research Institute, St Vincent's Clinical School, University of NSW, Darlinghurst, NSW, Australia.

PMID: 26170255
DOI: 10.1177/1087057115594589

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 C: omprehensive I: n Vitro P: roarrhythmia A: ssay (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.

Keywords: CiPA; Comprehensive In Vitro Proarrhythmic Assay; ICH E14; ICH S7B; QT interval; hERG; safety.

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

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

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