Desbutylhalofantrine: Evaluation of QT Prolongation and Other Cardiovascular Effects after Intravenous Administration In Vivo

Desbutylhalofantrine (Hfm) is an active and equipotent metabolite of halofantrine (Hf). Both compounds are effective in the treatment of sensitive and multidrug-resistant and In vitro data and interpretation of some clinical studies of Hf have suggested that, unlike Hf, Hfm may be devoid of adverse cardiac effects. The aim of these investigations was to provide the first in vivo examination of the intrinsic capacity of Hfm to affect repolarization in the heart, using an anesthetized rabbit model. Using a dose-rising regimen, Hfm was administered IV at doses of 1, 1, 2, 4, and 8 mg/kg and the baseline rate-corrected QT interval (QTc) value of 377 +/- 13 ms rose to 394 +/- 16, 396 +/- 12, 429 +/- 18, 433 +/- 16, and 489 +/- 15 ms, respectively. There were no significant changes in blood pressure, heart rate, or PR or QRS intervals. The Hfm plasma concentrations were quantitated after high-performance liquid chromatographic analysis, the results indicating a significant correlation between Hfm plasma concentration and QT(c) prolongation. The study also identified a concentration-dependent hemolysis of erythrocytes after administration of Hfm. The conclusions from this study are that IV administration of Hfm does cause a significant prolongation of the QT(c) interval in a rabbit model.