QT interval prolongation by noncardiovascular drugs: A proposed assessment strategy

The aim of the present article is to propose a pragmatic approach to the assessment of cardiac risk for noncardiovascular medicinal products. The clinical and pharmacological background to drug-induced cardiac arrhythmia is reviewed, in particular concerning the relationship between prolonged QT intervals in the ECG and often fatal torsades de pointes (TDP) in humans. In vitro and in vivo approaches are compared, and it is concluded that in vivo techniques are more appropriate for risk assessment, whereas in vitro techniques, including analysis of Purkinje fibers, are primarily useful for elucidating mechanisms. The study of monophasic action potentials (MAPs) is suggested to represent a useful bridge between in vitro and in vivo. A three-phase risk assessment strategy is proposed. The first phase uses telemetry in freely moving conscious dogs. If signs of QT prolongation or changes in T or U wave morphology are detected, this should be confirmed in a second phase by studying MAPs in anesthetized dogs under paced and nonpaced conditions (to rule out artifacts). Only if the presence of risk is confirmed should in vitro techniques, for example, analysis of Purkinje fibers, be employed for explanatory purposes. Drug Dev. Res. 47:55–62, 1999. © 1999 Wiley-Liss, Inc.