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Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

Journal Article · · PLoS ONE
 [1];  [2];  [2];  [3];  [4];  [5];  [2];  [6]
  1. U.S. Food and Drug Administration, Silver Spring, MD (United States); Univ. of Zaragoza, Zaragoza (Spain)
  2. U.S. Food and Drug Administration, Silver Spring, MD (United States)
  3. Univ. of Utah, Salt Lake City, UT (United States); Spaulding Clinical Research, West Bend, WI (United States)
  4. Stanford Univ., Palo Alto, CA (United States)
  5. Univ. of Zaragoza, Zaragoza (Spain); Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza (Spain)
  6. Univ. at Buffalo - The State Univ. of New York, Buffalo, NY (United States)
+ Show Author Affiliations

Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Furthermore, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.

Research Organization:
U.S. Food and Drug Administration, Silver Spring, MD (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1377847
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 12 Vol. 11; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (9)

Assessment of Multi‐Ion Channel Block in a Phase I Randomized Study Design: Results of the Ci PA Phase I ECG Biomarker Validation Study journal January 2019
Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study journal November 2017
Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk journal December 2016
Evaluating cardiac risk: exposure response analysis in early clinical drug development journal April 2018
Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk journal December 2017
QT Assessment in Early Drug Development: The Long and the Short of It journal March 2019
The Potential Role of the J‐T peak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium journal March 2019
Change and dispersion of QT interval during treatment with quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: results from the TEA trial journal November 2017
T vector velocity: A new ECG biomarker for identifying drug effects on cardiac ventricular repolarization journal July 2019

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Related Subjects

60 APPLIED LIFE SCIENCES
Phase I clinical investigation
biomarkers
calcium channels
decision tree
electrocardiography
heart rate
ion channels
potassium channels