Mechanism of cardiotoxicity of halofantrine

Objectives and Methods: To further evaluate the scope and mechanism of pote ntial cardiotoxicity associated with the antimalarial drug halofantrine, ca se reports submitted to the US Food and Drug Administration Spontaneous Rep orting System were examined, Because halofantrine was associated with elect rocardiographic prolongation of the QT interval and ventricular arrhythmias , in vitro cardiac electrophysiologic studies (isolated perfused cardiac mo del and isolated ventricular myocytes) were conducted to test the hypothesi s that halofantrine or its metabolite is responsible for cardiotoxicity, Results: Although it is difficult to ascertain causality and to estimate ov erall incidence, a significant number of adverse events related to the card iovascular system were reported, including QT interval prolongation, life-t hreatening arrhythmias, and sudden death. The effect of halofantrine and it s active metabolite (N-desbutylhalofantrine) on repolarization were examine d in an isolated perfused heart model. Results indicate that halofantrine w as able to prolong the QT interval, whereas N-desbutylhalofantrine had mini mal effect on the QT interval relative to baseline. In an attempt to furthe r elucidate the mechanism of QT interval prolongation, the effects of racem ic halofantrine, its stereoisomers, and N-desbutylhalofantrine on repolariz ing currents in isolated ventricular myocytes were studied with use of patc h-clamp techniques. Halofantrine produced a stereoselective block of the de layed rectifier potassium channel in isolated feline myocytes, Conclusions: These results indicate that halofantrine is similar to quinidi ne and class III antiarrhythmics in its ability to prolong repolarization. We conclude that high plasma concentrations of halofantrine should be avoid ed, especially in women, and that N-desbutylhalofantrine may have potential as a safer antimalarial drug.