MICE models: superior to the HERG model in predicting Torsade de Pointes

Area of Science:

• Cardiovascular pharmacology
• Ion channel research
• Drug safety assessment

Background:

• Drug-induced block of the hERG channel can cause lethal Torsade de Pointes (TdP) arrhythmias.
• Current hERG assays predict TdP with significant inaccuracy (approx. 30% discordance).
• There is a need for improved non-clinical methods to predict TdP risk.

Purpose of the Study:

• To evaluate if assaying multiple ion channel effects (MICE) improves TdP prediction accuracy.
• To compare the predictivity of MICE assays versus the standard hERG assay.
• To identify key ion channels for improved TdP risk assessment.

Main Methods:

• Concentration-response measurements of hERG, Nav1.5, and Cav1.2 currents for 55 drugs (32 torsadogenic, 23 non-torsadogenic).
• Utilized automated gigaseal patch clamp for high-throughput, accurate, and reproducible ion channel assays.
• Applied logistic regression models to compare MICE assay performance against the hERG assay.

Main Results:

• MICE assay models demonstrated a significant reduction in both false positives and false negatives compared to the hERG assay.
• The most effective MICE model required only assessing the blocking potencies of hERG and Cav1.2 channels.
• This suggests a synergistic effect or combined contribution of these channels in TdP induction.

Conclusions:

• The Multiple Ion Channel Effects (MICE) assay offers superior predictivity for drug-induced Torsade de Pointes compared to the sole hERG assay.
• Assessing combined effects on hERG and Cav1.2 channels is a promising strategy for enhanced drug safety evaluation.
• This approach can lead to more reliable non-clinical prediction of potentially lethal cardiac arrhythmias.