Drugs effects on ventricular repolarization: a critical evaluation of the strengths and weaknesses of current...

A growing number of drugs and drug combinations inhibit cardiac potassium ion conductance and ventricular repolarization, and increase cardiac APD, QT interval, and risk of potentially fatal TdP. The past decade has seen an explosion of research advances into the mechanism of action underpinning these observations, and an unprecedented level of collaboration between academia, industry, and regulatory authorities to define effective strategies for accurate prediction of increased TdP risk (if any) in humans, based upon nonclinical and/or clinical endpoints. Because the incidence of TdP is so very low, even for drugs for which the association is known, the risk can only be assessed based upon surrogate markers (signals) in in vitro and in vivo non-clinical studies as well as in clinical trials. In this article, we review both the strengths and weaknesses of current methodologies and regulatory practices for assessment of TdP risk for pharmaceuticals.