Minimizing repolarization-related proarrhythmic risk in drug development and clinical practice

Abstract

Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a major limitation to the development and use of new drugs. There are different types of drug-induced proarrhythmia, including long-QT syndrome (LQTS), short-QT syndrome and proarrhythmia related to Na+-channel blockade/conduction impairment. By far the most important form of proarrhythmia at present is drug-induced LQTS and its associated characteristic tachyarrhythmia, torsades de pointes (TdP). TdP arises when cellular action potentials (APs) are excessively prolonged, leading to arrhythmogenic afterdepolarizations, especially early afterdepolarizations (EADs), which trigger complex re-entry in a substrate involving increased transmural dispersion of repolarization. In vitro screening, increasingly involving high-throughput assays, is used to assess potential candidate molecules and eliminate potentially problematic structures at an early stage of development. The most commonly used screening assays assess drug block of the K+ current carried by human ether-à-go-go (hERG) subunits, corresponding to the rapid delayed-rectifier K+ channel, the overwhelmingly most common target of TdP-inducing drugs. In addition, the effects of drugs on AP duration or the in vivo equivalent, QT interval, are often assessed in animal models. Methods available for repolarization-related proarrhythmic risk assessment include in vitro (Langendorff-perfused rabbit or guinea pig hearts) and in vivo models (such as alpha-adrenoceptor-stimulated rabbits, rabbits with reduced repolarization reserve due to block of slow delayed-rectifier current, animals with chronic atrioventricular block or animals with cardiac remodelling caused by congestive heart failure). In silico modelling may be helpful for molecular design of non-hERG blocking candidates and for optimization of compound selection (at the molecular and pharmacological profile levels). Finally, clinical evaluation of effects on electrocardiographic intervals (particularly QT) and cardiac rhythm are often needed, both prior to drug approval and after successful introduction on the market (postmarketing surveillance). The successful avoidance of proarrhythmic complications is a shared responsibility of the innovative pharmaceutical industry, regulatory authorities, partners in the clinical drug development phase and practicing physicians. This paper reviews the principal forms of proarrhythmia and the methods that can be used to minimize the risk of proarrhythmia in drug development and clinical practice, with particular emphasis on the most common and problematic form, acquired LQTS.