Halofantrine stereoselective clearance and QT prolongation

To evaluate multiple-dose pharmacokinetics (PK) and pharmacodynamics (PD) of racemic halofantrine in healthy volunteers, 21 healthy subjects received halofantrine 500 mg by mouth daily for 43 days. Halofantrine concentrations were determined during this period and for an additional 137 days. Electrocardiograms (ECG) for QTc analysis were obtained at the time of each concentration determination. Results: Accumulation t1/2 (mean±SD) Steady State Oral (days) Clearance (ml/hr) (+)Halofantrine 16.5±38.1 3.37±1.73 (-)Halofantrine 17.2±36.3 4.78±3.17 QTc was prolonged in 12 of the 13 subjects who completed the study. Baseline QTc was 400.0±13.7 msec and mean QTc for the first 22 days of treatment was 422.6±19.9 msec (p<.002). A linear PK·PD model was used to relate (+) and (-) halofantrine concentration to QTc. Halofantrine at a dose proposed for malaria prophylaxis has marked stereoselective clearance and significantly prolongs ECG QTc in healthy volunteers.