QT interval prolongation by noncardiovascular drugs: A proposed assessmentstrategy

The aim of the present article is to propose a pragmatic approach to the as sessment of cardiac risk for noncardiovascular medicinal products. The clin ical and pharmacological background to drug-induced cardiac arrhythmia is r eviewed, in particular concerning the relationship between prolonged QT int ervals in the ECG and often fatal torsades de pointes (TDP) in humans. In v itro and in vivo approaches are compared, and it is concluded that in vivo techniques are more appropriate for risk assessment, whereas in vitro techn iques, including analysis of Purkinje fibers, are primarily useful for eluc idating mechanisms. The study of monophasic action potentials (MAPs) is sug gested to represent a useful bridge between in vitro and in vivo. A three-p hase risk assessment strategy is proposed. The first phase uses telemetry i n 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 ph ase by studying MAPs in anesthetized dogs under paced and nonpaced conditio ns (to rule out artifacts). Only if the presence of risk is confirmed shoul d in vitro techniques, for example, analysis of Purkinje fibers, be employe d for explanatory purposes. Drug Dev. Res. 47:55-62, 1999. (C) 1999 Wiley-L iss, Inc.