The significance of QT interval in drug development.

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