Mefloquine pharmacokinetic-pharmacodynamic models: Implications for dosingand resistance

Antimalarial resistance develops and spreads when spontaneously occurring m utant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not tho se with the resistance mutation(s). Mefloquine, a slowly eliminated quinoli ne-methanol compound, is the most widely used drug for the treatment of mul tidrug-resistant falciparum malaria. It has been used at doses ranging betw een 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has de veloped rapidly on the borders of Thailand, where the drug has been deploye d since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, earl y in the evolution of resistance, conventional assessments of the therapeut ic response less than or equal to 28 days after treatment underestimate con siderably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and w ould be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.