The significance of QT interval in drug development.

Abstract

The duration of QT interval of the surface electrocardiogram (ECG) reflects the ventricular action potential duration (APD) which is determined mainly by the rapid component of the outward repolarizing current (IKr). This current is mediated primarily by the delayed rectifying potassium channel. Thus, the QT interval is congenitally prolonged when this current is diminished as a result of genetic mutations of this channel as for example in the Romano–Ward syndrome [1]. Reduction in this current and hence, the prolongation of the QT interval may also be acquired, resulting from electrolyte imbalance (especially hypokalaemia and/or hypomagnesaemia), endocrine dysfunction (e.g. hypothyroidism), autonomic imbalance, various disease states or most frequently, following clinical administration of drugs. Drug-induced prolongation of the QTc interval may be followed by potentially fatal proarrhythmias. More than any other adverse drug reaction in recent times, it has been responsible for the withdrawal of many drugs from the market and yet as a surrogate of proarrhythmias, it is not well understood. Regulatory decisions have resulted in rejection of some new drugs or the restriction on the clinical use of many old and other new drugs over the last decade because of their potential to prolong the QTc interval. Therefore, there are regulatory and clinical expectations of better preapproval characterization of new chemical entities (NCEs) for this potential risk which have had a very profound influence on drug development. This paper will focus on the issues that need to be addressed during drug development, strategies aimed at identifying this risk during early preclinical and clinical phases of drug development and the regulatory assessment of the potential risk, particularly the electrocardiographic data from the clinical trials. Because the actually measured QT interval changes with heart rate in the absence of any intervention, it is usual to correct the measured interval for changes in heart rates (RR interval) to derive a rate-corrected (QTc) interval, which is then used when evaluating the effect of an intervention. Clinically, the rate-correction applied most widely, and almost exclusively for years, is the Bazett’s correction (QTc = QT/RR0.50), which divides the measured QT interval by the square root of the preceding RR interval. A less frequently applied rate-correction is that of Fridericia (QTc = QT/RR0.33) which divides the measured QT interval by the cube root of the preceding RR interval. Both these corrections standardize the measured QT interval to an RR interval of 1 s (heart rate of 60 beats min−1). When corrected by Bazett’s formula, on historical and epidemiological grounds, the widely accepted upper limits of normal QTc interval are 450 ms in adult males, 470 ms in adult females and 460 ms in children between 1 and 15 years of age (regardless of gender). Unless stated otherwise, the QTc interval referred to in this paper is the interval as corrected by Bazett’s formula. Drug-induced prolongation of QTc interval is expected with class III antiarrhythmic drugs which are intended to produce their desired therapeutic benefit by blocking IKr, delaying ventricular repolarization and, therefore, increasing myocardial refractory period. Typical examples of these drugs include sotalol, bretylium, ibutilide, dofetilide, azimilide, sematilide, ambasilide, almokalant, N-acetyl-procainamide, fenoxedil and terikalant.