[Electrocardiographic changes due to halofantrine in the treatment of malaria: therapeutic implications]

Electrocardiographic changes and their relationship with profiles of halofantrine (H) and desbutylhalofantrine (DBH) were assessed in a prospective study of 34 male patients with an uncomplicated falciparum malaria. H. was delivered in a one day in three intakes, 24 mg/kg/day. Seven days later the same regimen was administered. This study included a twelve-lead-electrocardiogram (to measure QTc interval), an ambulatory ECG monitoring a signal-averaged-electrocardiogram (to detect late ventricular potentials), and a kinetic-time profile of H. and DBH with high performance liquid chromatography. Data were obtained as follows: day 1 just prior to drug intake, 6 hours (H6), 12 hours (H12) after to drug delivery on day 1 and 8. There after on days 2, 3, 4, 9, 10, 11. Ambulatory ECG monitoring was recorded on day 1 and 8. QTc lengthening was noted in 10 patients with a mean QTc interval of 451 msec (range: 440-469 msec). Maximum QTc interval was obtained at H12 on day 1 (p < 0.0002) and 8 (p < 0.03). Signal-averaged electrocardiogram performed in 8 cases disclosed late potential in 4 cases (day 4: one case, day 9: 3 cases). No ventricular arrhythmia was observed on day 1 and 8. Plasma concentration time profile of H. showed a significant increase at day 8 H12 with a time effect (p < 0.0008) and a significant time-intake interaction (p < 0.02). QTc interval was significantly correlated with H. plasma level (p < 0.01) but not with D.B.H.. Late potentials were associated in 3 cases with a maximum plasma concentration level of H. These data showed that H. is potentially deleterious with a cardiac toxicity which appears dose-related, particularly during the second cure. Following this study, new prescription rules has been proposed before H. therapy.