Predicting thorough QT safety profile using hERG IC₁₀ versus IC₅₀

Area of Science:

• Pharmacology
• Cardiovascular Safety
• Drug Discovery

Background:

• The human ether-à-go-go-related gene (hERG) K+ channel is crucial for cardiac repolarization.
• Drug-induced QT prolongation is a major safety concern, with hERG channel inhibition being the primary mechanism.
• Current hERG IC50 assays require transformation into safety margins, which may not accurately reflect clinical risk at lower inhibition levels.

Purpose of the Study:

• To investigate the relationship between hERG inhibition and clinical QT prolongation (ΔΔQTc).
• To determine if inhibition metrics closer to therapeutic concentrations improve prediction of QT prolongation.
• To evaluate hERG IC10 as a direct predictor of QT liability.

Main Methods:

• Analysis of 44 drug/dose pairs correlating hERG inhibition with clinical ΔΔQTc.
• Comparison of hERG IC10 predictive performance against FDA safety margins derived from IC50.
• Logistic regression analysis to assess discrimination of ΔΔQTc ≥ 10 ms using IC10 versus IC50.

Main Results:

• Approximately 10-13% hERG inhibition corresponded to a 10 ms ΔΔQTc.
• hERG IC10 demonstrated comparable sensitivity and specificity to IC50-derived safety margins.
• Logistic regression using IC10 improved the prediction of ΔΔQTc UCI ≥ 10 ms (AUC 0.95 vs. 0.90).
• The predictive improvement by IC10 was attributed to its ability to account for drug-specific Hill slopes.

Conclusions:

• hERG IC10 serves as a direct index of QT liability, outperforming IC50-based safety margins for predicting clinical QT prolongation.
• Utilizing IC10 leverages differences in drug-specific Hill slopes for more accurate risk assessment.
• This approach enhances the prediction of ΔΔQTc liabilities at critical hERG inhibition levels around 10%.