An evaluation of hERG current assay performance: Translating preclinical safety studies to clinical QT prolongation

Block of delayed rectifier current (IKr, 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 (IC50 values for block/mean maximal plasma drug concentrations during TQT studies) were compared to QTc prolongation (QTc increase ≥ 5 ms). 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.