Referenced in: none

Automatically associated channels: Cav1.2 , Kv11.1 , Nav1.5

Title: MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes.

Authors: James Kramer, Carlos A Obejero-Paz, Glenn Myatt, Yuri A Kuryshev, Andrew Bruening-Wright, Joseph S Verducci, Arthur M Brown

Journal, date & volume: Sci Rep, 2013 , 3, 2100

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23812503

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.