MICE models: superior to the HERG model in predicting Torsade de Pointes.
Basic Information
ID: ALA3436045
Journal: Sci Rep
Title: MICE models: superior to the HERG model in predicting Torsade de Pointes.
Authors: Kramer J, Obejero-Paz CA, Myatt G, Kuryshev YA, Bruening-Wright A, Verducci JS, Brown AM.
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.
CiteXplore: 23812503
DOI: 10.1038/srep02100
Patent ID: ┄