Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines

Authors

  • H R Lu,

    Corresponding author
    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium
    Search for more papers by this author
  • E Vlaminckx,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium
    Search for more papers by this author
  • A N Hermans,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium
    Search for more papers by this author
  • J Rohrbacher,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium
    Search for more papers by this author
  • K Van Ammel,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium
    Search for more papers by this author
  • R Towart,

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium
    Search for more papers by this author
  • M Pugsley,

    1. Global Preclinical Toxicology/Pathology, Johnson & Johnson PR&D, Raritan, NJ, USA
    Search for more papers by this author
  • D J Gallacher

    1. Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development (PRD), a Division of Janssen Pharmaceutica NV, Beerse, Belgium
    Search for more papers by this author

  • This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.

Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Antwerp B-2340, Belgium. E-mail: hlu@prdbe.jnj.com

Abstract

Background and purpose:

The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K+ current (IKr), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a ‘first line’ test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here.

Experimental approach:

hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits.

Key results:

576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC50, 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 μM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts.

Conclusion and implications:

The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an ∼15–25% incidence of death.

British Journal of Pharmacology (2008) 154, 1427–1438; doi:10.1038/bjp.2008.191; published online 19 May 2008

Ancillary