Drug-induced QT interval prolongation: regulatory perspectives and drug development

Drug-induced torsade de pointes is a modern, iatrogenic challenge. This potentially fatal tachyarrhythmia is associated with many non-antiarrhythmic (including noncardiovascular) drugs, leading to a number of effective drugs being withdrawn from the market. Others have attracted severe prescribing restrictions while some new chemical entities have experienced difficulties in gaining regulatory approval. Since QT interval prolongation, a surrogate of torsade, is a mechanism-based concentration-dependent pharmacological effect, it is usually possible to characterise a drug for this toxicity during its development. The physicochemical and other pharmacological properties of a QT-prolonging drug modulate its clinical risk of torsade de pointes. Apart from these properties, the torsadogenic potential of a drug is also influenced clinically by a number of genetic and non-genetic factors. The former include polymorphisms of enzymes that metabolise the drug or its pharmacological target. Major non-genetic factors are the dose of the drug, co-medications especially metabolic inhibitors or other QT-prolonging drugs, presence of electrolyte imbalance and co-morbidity especially liver or cardiac disease, including pre-existing prolongation of the QT interval or bradycardia. Drug development programmes should be aimed at characterising the potency of a drug to prolong the OT interval and its interactions with these genetic and non-genetic variables, if valuable drugs are to gain approval and continue to be prescribed effectively and safely. Physicians too have an important role by ensuring that they adhere to prescribing information and monitor the patients as recommended.