Ketoconazole Halofantrine

Figure 2 Mean ( SE, n = 3) plasma concentration-time profile of halofantrine ( ) and desbutylhalofantrine ( ) after fasted oral administration of 150 mg Hf without keto-conazole (closed symbols) or after pretreatment with ketoconazole (open symbols). When Hf was co-administered with ketoconazole, the concentration of Hfm at all time points was below the LOQ of the assay, which was 10 ng/mL. 

Table 4 Summary Pharmacokinetic Parameters (mean SD, n = 3) for Halofantrine (Hf) and Desbutylhalofantrine (Hfm) After Oral Administration of Hf (150 mg) to Fasted Beagles with or without Coadministration of Ketoconazole... 

Halofantrine, a highly lipophilic antimalarial drug with poor and erratic absorption, is metabolized to its equi-potent metabolite desbutylhalofantrine and this is inhibited by oral ketoconazole (41). 

Khoo SM, Porter JH, Edwards GA, Charman WN. Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole. J Pharm Sci 1998 87(12) 1538 1. 

Clinically important, potentially hazardous interactions with amiodarone, astemizole, bepridil, carbamazepine, chloroquine, cisapride, clarithromycin, dihydroergotamine, disopyramide, ergotamine, grapefruit juice, halofantrine, haloperidol, itraconazole, ketoconazole, methadone, moxifloxacin, phenobarbital, phenytoin, pimozide, procainamide, quinidine, rifampicin, ritonavir, sotalol, St John s wort, telithromycin, terfenadine, voriconazole... 

K41.1 (ergl) KCNH2 7q35-36 minK, MiRPl Brain, heart, kidney, liver, lung, ovary, pancreas, testis, prostate, uterus, small intestine Astemizole, BeKM-1, ergtoxin, sertindole, dofetilide, cisapride, pimozide, terfenadine, halofantrine, BRL32872, E-4031, CT haloperidol, imipramine, cocaine, ketoconazole None... 

Pyrimethamine/sulfadoxine and tetracycline have been shown to increase halofantrine levels, and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine, and quinidine might also increase the toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with the concurrent use of potent CYP3A4 inhibitors. Fatty food markedly increases halofantrine levels, consequently it is recommended that halofantrine is taken on an empty stomach. Grapefruit juice has a similar effect Note that halofantrine is no longer widely marketed. 

A study in animals found that ketoconazole roughly doubled the AUC of halofantrine and inhibited its metabolism to the equipotent metabolite, desbutylhalofantrine. In in vitro studies, ketoconazole markedly inhibited the metabolism of halofantrine by CYP3A4. It has been suggested that the rise in halofantrine levels could reasonably be expected to increase toxicity. Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited the metabolism of halofantrine in vitro, and might therefore do so clinically. The manufacturer recommended caution with the concurrent use of potent CYP3A4 inhibitors. Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit the metabolism of halofantrine by CYP3A4, see (b) below. 

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