Evaluation of Drug-Induced QT Interval Prolongation

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Abstract
Assessment of proarrhythmic toxicity of newly developed drugs attracts significant attention from drug developers and regulatory agencies. Although no guidelines exist for such assessment, the present experience allows several key suggestions to be made and an appropriate technology to be proposed. Several different in vitro and in vitro preclinical models exist that, in many instances, correctly predict the clinical outcome. However, the correspondence between different preclinical models is not absolute. None of the available models has been demonstrated to be more predictive and/or superior to others. Generally, compounds that do not generate any adverse preclinical signal are less likely to lead to cardiac toxicity in humans. Nevertheless, differences in likelihood offer no guarantee compared with entities with a preclinical signal. Thus, the preclinical investigations lead to probabilistic answers with the possibility of both false positive and false negative findings. Clinical assessment of drug-induced QT interval prolongation is crucially dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. An integral part of this is a precise heart rate correction of QT interval, which has been shown to require the assessment of QT/RR relationship in each study individual. The numbers of electrocardiograms required for such an assessment are larger than usually obtained in pharmacokinetic studies. Thus, cardiac safety considerations need to be an integral part of early phase I/II studies. Once proarrhythmic safety has been established in phase I/II studies, large phase III studies and postmarketing surveillance can be limited to less strict designs. The incidence of torsade de pointes tachycardia varies from 1 to 5% with clearly proarrhythmic drugs (e.g. quinidine) to 1 in hundreds of thousands with drugs that are still considered unsafe (e.g. terfenadine, cisapride). Thus, not recording any torsade de pointes tachycardia during large phase III studies offers no guarantee, and the clinical premarketing evaluation has to rely on the assessment of QT interval changes. However, since QT interval prolongation is only an indirect surrogate of predisposition to the induction of torsade de pointes tachycardia, any conclusion that a drug is safe should be reserved until postmarketing surveillance data are reviewed. The area of drug-related cardiac proarrhythmic toxicity is fast evolving. The academic perspective includes identification of markers more focused compared with simple QT interval measurement, as well as identification of individuals with an increased risk of torsade de pointes. The regulatory perspective includes careful adaptation of new research findings.