Tropical Medicine and International Health VOLUME zyxwvutsrqponmlkj 2 NO. zyxwvutsrqponmlk 5 zyxwvutsrqponm PP 461-467 MAY 1997 zyxwvutsr ~~~ ~ ~ . . . . . ... . zyxwvu Efficacy of artemisinin and mefloquine combinations against zyxwv Plasmodium fulcipurum. In vitro simulation of in vivo pharmacokinetics B. Bwijo’, M. Hassan AlinZv3, N. Abbas’, W. Wernsdorfer4 and A. Bjorkman’.’ I Division of Infectious Diseases, Karolinska Instztutet, Huddinge, Sweden ’ Division of Infectious Diseases, Karolinska Instztutet, Danderyd, Sweden Division zyxwvutsrqpo of Biopharmaceutrcs zyxwvutsr e+ Pharmacokmetics, Uppsala University, Uppsala. Sweden Institute of Specific Prophylaxis & Tropical Medicine, University of Vienna, Vienna, Austria Summary The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine-sensitive (F32) strain of Plasmodium falciparum. A method of repetitive dosing and extending the culture observation period to 28-30 days was used to mimic the in vivo pharmacokinetic situation. Plasmodium falciparum was exposed to artemisinin from zy LO ~ to 10- M, mefloquine from 3 x to 10-5 M and their combinations. The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours. The drug-dosing duration was 3 days. Neither artemisinin nor mefloquine alone provided radical clearance of P. fakiparum, even when maximum concentrations (10 M) were applied. The antiparasitic activity of artemisinin and mefloquine were significantly higher when dosed alone. Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefloquine respectively were significantly lower when used in combination. At concentrations normally reached in uzuo, this effect was clearly synergistic (P=o.or 6) 3 days provides significant evidence of positive interaction between the two compounds. Lower combination concentrations around the MIC-values for the individual compounds 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. Our in uitro model of intermittent dosing of artemisinin and mefloquine combinations for keywords malaria, Plasmodium falciparum, artemisinin, mefloquine, combinations, in vitro correspondence Anders Bjorkman, Division of Infectious Diseases, Research Laboratories, F82, Huddinge University Hospital, S-141 86 Huddinge, Sweden Introduction There is today a need in malaria treatment to develop effective, safe and inexpensive new drugs. However, drug combinations that can be given as short courses to improve compliance, activity and possibly reduce costs are also important options. Combination therapy may also possibly protect the development of resistance to either or both drugs. Artemisinin or its derivatives are promising com- pounds used in areas where multidrug-resistant Plasmodium falciparum exists but the course of treatment has to be at least 5 days. Under field con- ditions, it is unlikely that patients would take a 46 I ( I997 Blackwell Science Ltd