Predicting Drug‐Induced QT Prolongation and Torsades de Pointes: A Review of Preclinical Endpoint Measures

Claire Townsend1, Barry S. Brown2

1 GlaxoSmithKline Biological Reagents and Assay Development, Research Triangle Park, North Carolina, 2 GlaxoSmithKline Safety Pharmacology, King of Prussia, Pennsylvania
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 10.16
DOI:  10.1002/0471141755.ph1016s61
Online Posting Date:  June, 2013
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Abstract

Compound‐induced prolongation of the cardiac QT interval is a major concern in drug development and this unit discusses approaches that can predict QT effects prior to undertaking clinical trials. The majority of compounds that prolong the QT interval block the cardiac rapid delayed rectifier potassium current, IKr (hERG). Described in this overview are different ways to measure hERG, from recent advances in automated electrophysiology to the quantification of channel protein trafficking and binding. The contribution of other cardiac ion channels to hERG data interpretation is also discussed. In addition, endpoint measures of the integrated activity of cardiac ion channels at the single‐cell, tissue, and whole‐animal level, including for example the well‐established action potential to the more recent beat‐to‐beat variability, transmural dispersion of repolarization, and field potential duration, are described in the context of their ability to predict QT prolongation and torsadogenicity in humans. Curr. Protoc. Pharmacol. 61:10.16.1‐10.16.19 © 2013 by John Wiley & Sons, Inc.

Keywords: cardiac ion channels; QT prolongation; hERG; drug discovery; safety

     
 
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Table of Contents

  • Introduction
  • Rapid Delayed Rectifier Potassium Channel
  • Other Cardiac Ion Channels
  • Action Potentials
  • QT Interval
  • Newer Endpoint Measures
  • Concluding Perspective
  • LITERATURE CITED
  • Tables
     
 
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Materials

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Literature Cited

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