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Title: Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk

Prolongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work demonstrated that separate analysis of the heart rate corrected J-T peakc (J-T peakc) and T peak-T end intervals can identify QTc prolonging drugs with inward current block and is being proposed as a part of a new cardiac safety paradigm for new drugs (the “CiPA” initiative). In this work, we describe an automated measurement methodology for assessment of the J-T peakc and T peak-T end intervals using the vector magnitude lead. The automated measurement methodology was developed using data from one clinical trial and was evaluated using independent data from a second clinical trial. Comparison between the automated and the prior semi-automated measurements shows that the automated algorithm reproduces the semi-automated measurements with a mean difference of single-deltas <1 ms and no difference in intra-time point variability (p for all > 0.39). In addition, the time-profile of the baseline and placebo-adjusted changes are within 1 ms for 63% of the time-points (86% within 2 ms). Importantly, the automated results lead tomore » the same conclusions about the electrophysiological mechanisms of the studied drugs. We have developed an automated algorithm for assessment of J-T peakc and T peak-T end intervals that can be applied in clinical drug trials. Under the CiPA initiative this ECG assessment would determine if there are unexpected ion channel effects in humans compared to preclinical studies. In conclusion, the algorithm is being released as open-source software.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1]
  1. US Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research, Office of Clinical Pharmacology
  2. US Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research, Office of Clinical Pharmacology; Univ. of Zaragoza (Spain). Aragon Inst. for Engineering Research (I3A), Inst. de Investigacion Sanitaria Aragon (IIS Aragon)
Publication Date:
Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 12; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Research Org:
US Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1378470