Pharmacodynamic interaction between atovaquone and other antimalarial compounds against Plasmodium falciparum in vitro

Atovaquone, a 2-hydroxy-1,4-naphthoquinone, was first introduced as a drug against opportunistic infections in immuno-compromised patients. Early clinical-parasitological experiences in the treatment of malaria were disappointing due to highly variable and poor absorption, a phenomenon typical for naphthoquinones. Proguanil was found to potentiate the activity of atovaquone and the combination of the two drugs was introduced as an antimalarial drug with blood schizontocidal and causal prophylactic activity. It is now widely used in therapy and prophylaxis. Despite the enhanced activity, the combination does not always overcome the problem of poor absorption of atovaquone, especially in the presence of gastro-intestinal disorders. Therefore, further combination with a fast-acting blood schizontocide, e.g. one of the artemisinins, could accelerate clinical improvement and normalization of absorption. The interaction between artemisinin and atovaquone and that of artemisinin and atovaquone + proguanil has been investigated in 37 fresh isolates of Plasmodium falciparum from northwestern Thailand, an area with high prevalence of multi-drug resistance. Interaction between atovaquone and artemisinin was synergistic above the EC30, with mean Sigma FIC (Berenbaum) values of 0.9679 at the EC50, 0.4014 at the EC90 and 0.2214 at the EC99. Synergism was more pronounced with the triple combination, i.e. atovaquone + proguanil and artemisinin, starting at the EC10 level. The mean Sigma FIC values were 0.7626 at the EC50, 0.2939 at the EC90, and 0.1527 at the EC99. The strong synergism at the therapeutically relevant effective concentrations suggests that the therapeutic efficacy of atovaquone-proguanil can be considerably enhanced by the additional administration of a suitable artemisinin derivative, e.g. artesunate.