In vitro evaluation of 10 drugs showed prominent hERG inhibition (>50% for 9/10 drugs) despite wide action potential duration changes, suggesting neither assay alone predicts proarrhythmic risk.
Do hERG and repolarization assays adequately predict proarrhythmic risk for drugs with multi-channel block?
The hERG assay alone is insufficient to predict proarrhythmic risk for drugs that exhibit multi-channel block, as it oversimplifies the complex repolarization process.
Drug-induced delayed cardiac repolarization is a recognized risk factor for proarrhythmia and is associated with block of IKr (the potassium current encoded by the human ether-a- go-go-related gene hERG). To evaluate the utility of 2 in vitro assays widely used to assess delayed repolarization, we compared the effects of haloperidol and 9 structurally diverse drugs in a hERG and repolarization (canine Purkinje fiber action potential duration APD) assay over wide concentrations. Despite potent hERG current block (IC50 = 0.174 microM), haloperidol elicited a bell-shaped concentration-response relationship for APD prolongation, with lesser prolongation (and reduced plateau height) observed with concentrations eliciting maximal hERG block, consistent with multi-channel block at higher concentrations. Consistent with this hypothesis, APD prolongation with the specific IKr blocker dofetilide was a) reduced by concomitant administration of nifedipine (calcium current block) and b) reversed by lidocaine (late sodium current block). Additional studies demonstrated prominent (>50%) hERG inhibition with most (9/10) drugs despite wide APD changes (158% prolongation - 16% shortening), consistent with multi-channel block. The poor correlation between hERG and repolarization assays suggests that the hERG assay oversimplifies drug effects on the complex repolarization process for drugs demonstrating multi-channel block and that neither assay alone adequately predicts proarrhythmic risk.
Martin et al. (Thu,) conducted a other in Drug-induced delayed cardiac repolarization. Haloperidol and 9 structurally diverse drugs was evaluated on hERG current block and action potential duration (APD). In vitro evaluation of 10 drugs showed prominent hERG inhibition (>50% for 9/10 drugs) despite wide action potential duration changes, suggesting neither assay alone predicts proarrhythmic risk.