Mefloquine Ketoconazole

Clinically important, potentially hazardous interactions with chloroquine, ketoconazole, mefloquine, nilotinib, sulpiride... 

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. 

Ketoconazole increased the AUC of mefloquine by 79%. The clinical relevance of this is uncertain, but an increase in adverse events is possible. 

In a study in healthy subjects a single 500-mg dose of mefloquine, given on day 5 of a 10-day course of ketoconazole 400 mg daily, increased the mefloquine AUC by 79%, the maximum level by 64% and the half-life by 34%, when compared to mefloquine alone. A 28% decrease in the AUC of the carboxylic metabolite was also seen. No significant adverse effects were reported. It is probable that ketoconazole inhibits the metabolism of mefloquine by cytochrome P450 isoenzyme CYP3A4. Although the clinical relevance of this increase in mefloquine levels is not known, it seems possible that it could increase the risk of adverse effects in some patients. Until more is known, it may be prudent to be cautious in the use of mefloquine in patients taking ketoconazole. 

Ridtitid W, Wongnawa M, Mahatthanatrakul W, Raungsri N, Sunbhanich M. Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers. J Clin Pharm Ther (2005) 30, 285-90. 

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