Effects of prior administration of amodiaquine on the disposition of halofantrine in healthy volunteers.

The prevalence of multidrug-resistant malaria parasites brings about the switch from an antimalarial drug with poor therapeutic outcome to an effective alternative, resulting in overlap in the plasma drug levels. In this study, the influence of prior administration of amodiaquine on the pharmacokinetics and electrocardiographic effect of halofantrine (HF) was investigated in healthy volunteers. Ten healthy male subjects were each given single oral doses of 500 mg HF alone or with 600 mg of amodiaquine hydrochloride (AQ) administered 24 hours before the HF dose in a crossover fashion. Blood samples, collected at predetermined time intervals, were analyzed for HF and its major metabolite, desbutylhalofantrine (HFM) using a validated high-performance liquid chromatography method. Electrocardiogram for each volunteer was taken at predetermined time points. Results showed that prior administration of amodiaquine resulted in no significant changes (P > 0.05) in any of the pharmacokinetic parameters of HF. For example, the parameter values for HF alone and with AQ were: Cmax 144 +/- 53 versus 164 +/- 58 microg/L; T1/2beta 142 +/- 23 versus 139 +/- 28 hours; Cl/F 37.3 +/- 13.9 versus 32.3 +/- 11.4 L/h; and metabolic ratio 1.2 +/- 0.5 vs 1.1 +/- 0.6 Similarly, the disposition of HFM was not significantly altered (P > 0.05) after an earlier exposure to amodiaquine. In addition, the presence of AQ was linked with a further lengthening of the QT interval compared with the effect of HF alone. This study suggests that prior administration of AQ does not result in a significant alteration of the pharmacokinetics of HF but may be associated with an increased risk of QT prolongation. It may be necessary to exercise caution in the use of HF for malaria treatment in persons who have recently received AQ.