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

TLDR

Drug‑induced hERG channel block delays cardiac repolarization and increases Torsade de Pointes risk, yet regulatory reliance on a positive hERG assay yields about 30 % discordance. The study tests whether measuring block of multiple ion channels (MICE) improves TdP prediction compared to hERG alone. Concentration–response data for hERG, Nav1.5, and Cav1.2 were collected for 55 drugs using automated gigaseal patch‑clamp to enable high‑throughput, accurate, reproducible assays. MICE‑based logistic regression markedly lowered both false positives and false negatives relative to hERG alone, with the optimal model requiring only hERG–Cav1.2 potency comparison.

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.