Drug-induced prolongation of the QT interval: Present and future challenges for drug discovery

Abstract

Delayed repolarization (manifest as prolongation of the QT interval) is a well-established surrogate marker for a rare but potentially lethal arrhythmia termed torsade de pointes (TdP). Numerous preclinical assays have been developed to detect liabilities associated with drug-induced delayed repolarization across multiple levels of integration (including subcellular, cellular, organ, whole animals) and species (including humans). Off-target effects of noncardiovascular drugs (e.g., terfenadine, cisapride) include block of I Kr (also known as Kv11.1 or hERG), a repolarizing potassium current that plays a prominent role in ventricular repolarization. While contributing to the genesis of TdP, additional drug effects on other cardiac currents that modulate repolarization across different preclinical models must be considered when characterizing drug-induced delayed repolarization and translating proarrhythmic risk to humans. This chapter describes the basis for this important cardiovascular liability facing all small molecule drug candidates, various preclinical proarrhythmia models available to characterize proarrhythmic risk related to delayed repolarization, and evolving future approaches focused on cellular and subcellular mechanism-based in vitro and in silico evaluations of proarrhythmia.