Clinical application of mefloquine pharmacokinetics in the treatment of P falciparum malaria.

Malaria remains a major public health problem in large areas of the world. One of the major factors responsible for the resurgence is the emergence of Plasmodium falciparum, resistant to available antimalarials. An antimalarial, mefloquine, has been considered since its introduction as a promising alternative antimalarial drug to overcome the situation of widespread multidrug resistant P falciparum. Pharmacokinetic studies of mefloquine have been investigated in several groups of subjects either as mefloquine alone or as combined regimens. The oral absorption of mefloquine is relatively rapid, reaching peak concentrations within 24 hours. Metabolism takes place in the liver, with carboxymefloquine as a major metabolite. Mefloquine has a large apparent volume of distribution of 200 L and is highly bound (98%) to plasma proteins. The elimination is slow; the terminal half-life is 13 10 to 14 days in Thai patients with falciparum malaria. Vomiting within 1 hour of drug administration has an influence on blood concentrations of mefloquine and this may result in treatment failure. The whole blood concentrations of mefloquine on the first two days of treatment are important determinants of parasitological response. There appear to be no pharmacokinetic interactions between mefloquine and the other two components of Fansimef in patients with uncomplicated falciparum malaria. The advantage of this combination over mefloquine alone in multidrug resistant P falciparum is still debatable. However, recent data seem to support the higher efficacy of Fansimef over mefloquine alone. Concurrent administration of antibiotics, ie ampicillin and tetracycline with mefloquine results in a significant increase in maximum concentration, reduction of the apparent volume of distribution and shortening of the terminal elimination half-life of mefloquine. An antiemetic drug metoclopramide accelerates the absorption of mefloquine and increases the maximum concentration. In contrast, mefloquine concentrations are decreased in the presence of an antimalarial, artesunate. Primaquine has no effect on the pharmacokinetics of mefloquine when given concurrently.