Omoruyi et al. (2007) studied the effects of amodiaquine on the pharmacokinetics of halofantrine in 10 healthy Nigerian males, using a cross over design with an 8-week washout. Subjects received a single oral dose of 500 mg halofantrine with or without pre-administered amodiaquine, given as a single 600 mg oral dose 1 day prior. The major findings were a lack of any observable or statistical change in the Tmax (6 vs. 7 h), Cmax (144 ± 53 vs. 164 ± 58 μg/L, mean ± SEM), t1/2 (142 ± 23 vs. 139 ± 28), or AUC_∞ (14,932 ± 4,932 vs. 17,329 ± 5,988 μg h/L) for halofantrine vs. combined therapy, respectively. Little differences were observed for desbutylhalofantrine, the major metabolite, with respect to Tmax, Cmax, mean residence time, and AUC, when subjects were given halofantrine or in combination with amodiaquine. It has been shown, in vitro, that human CYP3A4 and CYP3A5 are major isoenzymes responsible for the N-debutylation of halofantrine (Baune et al. 1999) and amodiaquine is a weak inhibitor of these enzymes (Bapiro et al. 2001; Baune et al. 1999), supporting the lack of pharmacokinetic interaction observed in this study. However, there was significant variability, which in conjunction with the relatively small and sample size, could have yielded false negative findings. As well, only single doses of halofantrine and amodiaquine were used, which may not reflect the true clinical, steady-state, situation where subjects would be given multiple doses of either agent. Despite the lack of pharmacokinetic interaction, however, the authors did note a prolongation of QT interval in the combination group compared to subjects on halofantrine alone, indicating a pharmacodynamic effect that appears to be unrelated to any pharmacokinetics interaction. These observations, however, need to be confirmed in the actual patient population (Table 6.1).