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.


CONCLUSIONS
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.
Raschi
Emanuel
E
University of Bologna, Department of Pharmacology, Italy.
Ceccarini
Luisa
L
De Ponti
Fabrizio
F
Recanatini
Maurizio
M
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D006801:Humans; D018570:Risk Assessment / Q000379:methods; D016171:Torsades de Pointes / Q000139:chemically induced*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human