HERG block, QT liability and sudden cardiac death

Abstract

Non-cardiac drugs may prolong action potential duration (APD) and QT leading to Torsade de Pointes (TdP) and sudden cardiac death. TdP is rare and QT is used as a surrogate marker in the clinic. For non-cardiac drugs, APD/QT liability is always associated with a reduction in hERG current produced by either direct channel block or inhibition of trafficking. hERG and APD liabilities correlate better when APDs are measured in rabbit versus canine Purkinje fibres. hERG and APD/QT liabilities may be dissociated when hERG block is offset by block of calcium or sodium currents. hERG liability may be placed in context by calculating a safety margin (SM) from the IC50 for inhibition of hERG current measured by patch clamp divided by the effective therapeutic plasma concentration of the drug. The SM is uncertain because literature values for IC50 may vary by 50-fold and small differences in plasma protein binding have large effects. With quality control, the IC50 95% confidence limits vary less than twofold. Ideally, hERG liability should be determined during lead optimization. Patch damp has insufficient throughput for this purpose. A novel high-throughput screen has been developed to detect drugs that block hERG directly and/or inhibit hERG trafficking.