Reducing QT liability and proarrhythmic risk in drug discovery and development

Drug-induced torsades de pointes (TdP), a rare, life-threatening, polymorphic, ventricular tachycardia associated with prolongation of the QT interval, has been the main safety reason for the withdrawal of medicines from clinical use over the last decade. Most often, drugs that prolong the action potential and delay ventricular repolarization do so through blockade of outward (repolarizing) currents, predominantly the rapid delayed rectifying potassium current, I-Kr. While QT interval prolongation is not a safety concern per se, in a small percentage of people, it has been associated with TdP, which either spontaneously terminates or degenerates into ventricular fibrillation. Furthermore, recent data suggest that shortening of the QT interval may also be a new safety issue waiting to surface. This review article summarizes the presentations given at a symposium entitled 'Reducing QT liability and proarrhythmic risk in drug discovery and development', which was part of the Federation of the European Pharmacological Societies congress, Manchester, UK, 13-17 July 2008. The objective of this symposium was to assess the effects of implementing the latest regulatory guidance documents (International Conference on Harmonization S7A/B and E14), as well as new scientific and technical trends on the ability of the pharmaceutical industry to reduce and manage the QT liability and associated potential proarrhythmic risk, and contribute to the discovery and development of safer medicines. This review outlines the key messages from communications presented at this symposium and attempts to highlight some of the key challenges that remain to be addressed. British Journal of Pharmacology (2010) 159, 5-11; doi:10.1111/j.1476-5381.2009.00547.x