MICE Models: Superior to the HERG Model in Predicting Torsade De Pointes

Sci Rep. 2013;3:2100. doi: 10.1038/srep02100.

Abstract

Drug-induced block of the cardiac hERG (human Ether-à-go-go-Related Gene) potassium channel delays cardiac repolarization and increases the risk of Torsade de Pointes (TdP), a potentially lethal arrhythmia. A positive hERG assay has been embraced by regulators as a non-clinical predictor of TdP despite a discordance of about 30%. To test whether assaying concomitant block of multiple ion channels (Multiple Ion Channel Effects or MICE) improves predictivity we measured the concentration-responses of hERG, Nav1.5 and Cav1.2 currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple classes. We used automated gigaseal patch clamp instruments to provide higher throughput along with accuracy and reproducibility. Logistic regression models using the MICE assay showed a significant reduction in false positives (Type 1 errors) and false negatives (Type 2 errors) when compared to the hERG assay. The best MICE model only required a comparison of the blocking potencies between hERG and Cav1.2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / physiology*
  • Humans
  • Models, Theoretical*
  • Patch-Clamp Techniques
  • Predictive Value of Tests
  • Torsades de Pointes / diagnosis
  • Torsades de Pointes / physiopathology*

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human