Block of delayed rectifier current (I(Kr), Kv11.1 encoding the hERG gene) is associated with delayed cardiac repolarization (QTc prolongation), a surrogate marker of proarrhythmia. Despite its recognized role in assessing QTc prolongation risk, a quantitative analysis of the utility and limitations of the hERG current assay has not been reported. To benchmark hERG assay performance, this retrospective study compared hERG block potency with drug-induced QTc prolongation assessed during rigorous thorough QT (TQT) clinical studies for 39 drugs from multiple classes. To place block in context, hERG safety margins (IC(50) values for block/mean maximal plasma drug concentrations during TQT studies) were compared to QTc prolongation (QTc increase≥5ms). Most (9/10) drugs eliciting essentially no hERG block at maximal concentrations demonstrate no QTc prolongation despite representing a wide hERG safety margin range. Based on receiver-operator characteristics, a hERG safety margin of 45 provided optimal overall performance linking safety margins to QTc prolongation (sensitivity (true positive rate)=0.64, specificity (true negative rate)=0.88); the area under the receiver-operator curve (0.72) is indicative of moderate overall concordance. Likelihood ratios calculated from multitier contingency tables suggest that QTc prolonging drugs are only 5-7 times as likely to demonstrate low safety margins (1-30 range) compared to drugs that do not prolong QTc. Paradoxically, higher safety margins demonstrate lesser confidence predicting prolongation. The overall limitations of hERG safety margins shown using these quantitative, evidence-based approaches highlight the need for additional preclinical assays and adaptive strategies throughout drug discovery to reliably mitigate QTc prolongation risk.
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