hERG-related drug toxicity and models for predicting hERG liability and QT prolongation

BACKGROUND: hERG K(+) channels have been recognized as a primary antitarget in safety pharmacology. Their blockade, caused by several drugs with different therapeutic indications, may lead to QT prolongation and, eventually, to potentially fatal arrhythmia, namely torsade de pointes. Therefore, a number of preclinical models have been developed to predict hERG liability early in the drug development process. OBJECTIVE: The aim of this review is to outline the present state of the art on drug-induced hERG blockade, providing insights on the predictive value of in vitro and in silico models for hERG liability. METHODS: On the basis of latest reports, high-throughput preclinical models have been discussed outlining advantages and limitations. CONCLUSION: Although no single model has an absolute value, an integrated risk assessment is recommended to predict the pro-arrhythmic risk of a given drug. This prediction requires expertise from different areas and should encompass emerging issues such as interference with hERG trafficking and QT shortening.