Improving the assessment of heart toxicity for all new drugs through translational regulatory science.

Published

Journal Article

Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

Full Text

Duke Authors

Cited Authors

  • Johannesen, L; Vicente, J; Gray, RA; Galeotti, L; Loring, Z; Garnett, CE; Florian, J; Ugander, M; Stockbridge, N; Strauss, DG

Published Date

  • May 2014

Published In

Volume / Issue

  • 95 / 5

Start / End Page

  • 501 - 508

PubMed ID

  • 24336137

Pubmed Central ID

  • 24336137

Electronic International Standard Serial Number (EISSN)

  • 1532-6535

International Standard Serial Number (ISSN)

  • 0009-9236

Digital Object Identifier (DOI)

  • 10.1038/clpt.2013.238

Language

  • eng