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Clin Pharmacol Ther. 2018 Jan;103(1):54-66. doi: 10.1002/cpt.896. Epub 2017 Nov 16.

Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study.

Author information

1
Office of New Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA.
2
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA.
3
Department of Medicine, Division of Cardiology, University of Utah, Salt Lake City, Utah, USA.
4
Spaulding Clinical Research, West Bend, Wisconsin, USA.
5
Stanford University, Palo Alto, California, USA.

Abstract

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

PMID:
28986934
PMCID:
PMC5765372
DOI:
10.1002/cpt.896
[Indexed for MEDLINE]
Free PMC Article

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