Pharmacological and Regulatory Aspects of QT Prolongation

The long and growing list of non-antiarrhythmic drugs associated with prolongation of the QT interval of the electrocardiogram has generated concern not only for regulatory interventions leading to drug withdrawal, but also for the unjustified view that QT prolongation is usually an intrinsic effect of a whole therapeutic class (e.g. antihistamines), whereas, in many cases, it is displayed only by some compounds within a given class of non-antiarrhythmic drugs because of an effect on cardiac repolarisation. This chapter provides insight into the strategies that should be followed during a drug development program when a drug is suspected of affecting the QT interval, with specific emphasis on the factors limiting the predictive value of preclinical and clinical studies (in silico studies are covered in other chapters). Mechanisms leading to QT prolongation (which are not limited to hERG blockade) are briefly discussed from a pharmacological point of view. The chapter also highlights the requirements of clinical studies: although prolongation of the QT interval by non-antiarrhythmic drugs is not an unusual finding, potentially fatal arrhythmias such as TdP are uncommon and are unlikely to occur during phase I-III clinical trials, when relatively small numbers of subjects are exposed to the investigational drug. Thus, QT prolongation has become a surrogate marker of cardiotoxicity and has received increasing regulatory attention. An important, unresolved problem is that there is no consensus on the degree of QT prolongation to be considered clinically significant and on the need of the so-called “thorough QT study”.