Drug-induced prolongation of the QT interval: regulatory dilemmas and implications for approval and labelling of a new chemical entity.

QT interval of the electrocardiogram (ECG) reflects the duration of the ventricular action potential. It is prolonged usually when there is delayed repolarisation due to diminished outward potassium current during phase 2 and 3 of the action potential. Clinically, it is an important pharmacological effect of a drug. This effect, when exerted in a carefully controlled manner, is the primary pharmacological mechanism by which class III anti-arrhythmic drugs exert their beneficial effect. However, QT interval prolongation, when excessive, can be pro-arrhythmic and can degenerate into torsade de pointes (TdP), a unique polymorphic form of ventricular tachycardia [1]. Apart from clinical manifestations resulting from impaired circulation, TdP is potentially fatal. TdP subsequently degenerates into ventricular fibrillation in about 20% of cases [2] and, not uncommonly, cardiac arrest and sudden death may be the outcome [3]. The overall mortality is of the order of 10–17% [2,4]. Drug-induced prolongation of QT interval is therefore a highly undesirable pharmacological effect as far as non-antiarrhythmic drugs are concerned. A number of antianginal drugs as well as non-cardiovascular drugs have been shown to carry this concentration-related liability. There are now well over 10 antianginal and 80 noncardiac drugs, which have been reported to significantly prolong the QT interval and/or induce TdP. It is recognised that QT interval prolongation per se is not necessarily harmful. However, when excessive, it can degenerate into TdP and the risk of induction of TdP bears an exponential relationship to the degree of prolongation. The link between QT interval prolongation and TdP is complex and influenced by many other factors. Not all the drugs prolonging the QT interval, or blocking the outward repolarising potassium current, to the same extent carry the same torsadogenic risk. Drugs such as amiodarone and racemic sotalol prolong the QT interval but their torsadogenic potential is nowhere near as high as one might anticipate. Other ancillary pharmacological properties of these drugs no doubt modulate their torsadogenic risk. Myxoedema is also associated with prolongation of QT interval but this is not a disease that one typically associates with TdP. Notwithstanding, QT interval is the best surrogate marker we currently