Stereoselective halofantrine disposition and effect: concentration-relatedQTc prolongation

Aims 1) To characterize the variability of multiple-dose halofantrine pharm acokinetics over time in healthy adults, 2) to correlate the pharmacodynami c measure electrocardiographic (ECG) QT interval with (+)- and (-)-halofant rine plasma concentration and 3) to evaluate the safety and tolerance of ha lofantrine hydrochloride given over tints to healthy adults. Methods Twenty-one healthy subjects were enrolled and 13 completed the stud y (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine wa shout was documented for the following 138 days. Pharmacokinetic and pharma codynamic (ECG QTc) measurements were obtained. Results Mean accumulation half-times (days) for halofantrine were: 7.0 +/- 4.8 [(+)- halofantrine] and 7.3 +/- 4.8 [(-)-halofantrine]. Mean steady-sta te concentrations were. 97.6 +/- 52.0 ng ml(-1) [( +)-halofantrine] and 48. 5 +/- 20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139 +/- 73 l h(-1) [(+)-halofantrine] and 265 +/- 135 l h(-1) [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4-8 h following drug administrat ion. Fourteen of 16 subjects who received active drug had ECG QTc prolongat ion that was positively correlated with both (+)- and (-)-halofantrine conc entration. The five subjects who received placebo had no demonstrable chang e in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubjec t pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.