EFFICACY OF ARTEMISININ AND MEFLOQUINE COMBINATIONS AGAINST PLASMODIUM-FALCIPARUM - IN-VITRO SIMULATION OF IN-VIVO PHARMACOKINETICS

The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine-sensitive (F32) strain of Plasmodium fa lciparum. A method of repetitive dosing and extending the culture obse rvation period to 28-30 days was used to mimic the in vivo pharmacokin etic situation. Plasmodium falciparum was exposed to artemisinin from 10(-8) to 10(-5) M, mefloquine from 3 x 10(-9) to 10(-5) M and their c ombinations. The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours. The drug-dosing duration was 3 days. Nei ther artemisinin nor mefloquine alone provided radical clearance of P. falciparum, even when maximum concentrations (10(-5) M) were applied. The antiparasitic activity of artemisinin and mefloquine were signifi cantly higher when dosed alone. Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefl oquine respectively were significantly lower when used in combination. At concentrations normally reached in vivo, this effect was clearly s ynergistic (P=0.016). Our in vitro model of intermittent dosing of art emisinin and mefloquine combinations for 3 days provides significant e vidence of positive interaction between the two compounds. Lower combi nation concentrations around the MIC-values for the individual compoun ds showed synergistic effect, and high concentrations showed additive effect. This indicates that such drug combinations may provide radical clearance at concentrations lower than those required for single-drug treatment.