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J Electrocardiol. 2018 Aug 7. pii: S0022-0736(18)30387-X. doi: 10.1016/j.jelectrocard.2018.08.003. [Epub ahead of print]

Update on the ECG component of the CiPA initiative.

Author information

1
Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA. Electronic address: jose.vicenteruiz@fda.hhs.gov.

Abstract

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is validating a new paradigm for assessing proarrhythmic potential of drugs that goes beyond hERG block and QT prolongation. Based on in vitro data of the drug's effects on multiple cardiac ion channel currents, CiPA's in silico model of the human cardiomyocyte will classify drugs as low, intermediate or high risk for torsade de pointes. Under CiPA, early phase 1 ECG data will be used to determine if there are unexpected ion channel effects in humans compared to the in vitro ion channel data. CiPA's ECG biomarker working group identified the heart rate corrected J-Tpeak interval (J-Tpeakc, from the end of the QRS to the peak of the T-wave) as the best of 12 ECG biomarkers to detect late sodium current block in presence of hERG block. While predominant hERG blockers prolonged QTc and J-Tpeakc, "balanced" ion channel blocking drugs (hERG + late sodium and/or calcium block) prolonged QTc without prolonging J-Tpeakc. This manuscript reviews the ECG component of CiPA and provides a description of the ECG methods used in the CiPA ECG validation clinical study.

KEYWORDS:

J-Tpeakc; Multi-ion channel block; QTc prolongation; Torsade de pointes; hERG block

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