Pharmacokinetic interaction trial between co-artemether and mefloquine

Forty-two healthy subjects were randomized in a parallel three-group design trial to investigate potential electrocardiographic and pharmacokinetic in teractions between the new antimalarial co-artemether, a combination of art emether and lumefantrine (both of which are predominantly metabolized throu gh CYP3A4), and mefloquine, another antimalarial described as a substrate ( and possible inhibitor) of CYP3A4. Subjects were assigned to one of the thr ee possible treatment groups (i.e., co-artemether alone or mefloquine alone or the combination of both). The dosage was 1000 mg mefloquine (divided in to three doses over 12 h) followed 12 h later by six applications of co-art emether (40 mg artemether+480 mg lumefantrine each) over 60 h. The study me dications were generally well tolerated after all treatments. Concomitant a dministration with mefloquine caused statistically significant lower (aroun d 30-40%) plasma concentrations of lumefantrine than when co-artemether was administered alone. Even if important, this decrease in lumefantrine expos ure was considered unlikely to impact clinical efficacy given the wide ther apeutic index of co-artemether and the usual high variability in lumefantri ne plasma levels, mostly and more importantly influenced by food intake. Ho wever. patients should be encouraged to eat at dosing times to compensate f or this decreased bioavailability. The pharmacokinetics of artemether, DHA or mefloquine were not affected. Artemether concentrations significantly de creased over doses, independently of mefloquine co-administration, while DH A concentrations slightly (not significantly) increased. Therefore, no clin ically relevant risks due to pharmacokinetic drug-drug interaction are expe cted at the enzymatic level following co-administration of co-artemether wi th CYP3A4 substrates with similar affinity to that of mefloquine. (C) 2000 Elsevier Science B.V. All rights reserved.