Atovaquone/Proguanil

Abstract

Atovaquone/proguanil is a fixed-dose combination tablet of two antimalarial agents and is highly effective for the prevention of Plasmodium falciparum malaria. In combination with proguanil, the ability of atovaquone to inhibit parasitic mitochondrial electron transport is markedly enhanced. Both atovaquone and proguanil are active against hepatic (pre-erythrocytic) stages of P. falciparum, thereby providing causal prophylaxis and eliminating the need to continue post-travel treatment beyond 7 days. Both agents are also active against erythrocytic stages of P. falciparum, thereby providing suppressive prophylaxis. Atovaquone/proguanil is highly effective against drug-resistant strains of P. falciparum, and cross-resistance has not been observed between atovaquone and other anti-malarial agents. In comparative, randomised clinical trials, there were no cases of P. falciparum malaria in nonimmune adults, adolescents and children (≥11kg) visiting malaria-endemic regions for ≤28 days and receiving atovaquone/proguanil (250/100mg in adults and dosage based on body weight in children P. falciparum malaria was estimated at 100% for atovaquone/proguanil and for mefloquine, and 70% for chloroquine plus proguanil. In individuals (≥11kg) from endemic regions who may carry some immunity to malaria (semi-immune), the prophylactic efficacy rating for atovaquone/proguanil based on placebo-controlled trials was 95–100%. Atovaquone/proguanil is generally well tolerated by both adults and children. The most common treatment-related adverse events in placebo-controlled trials were headache and abdominal pain, which occurred at a rate similar to that observed with placebo. Atovaquone/proguanil therapy was associated with significantly fewer gastrointestinal adverse events than chloroquine plus proguanil, and significantly fewer neuropsychiatric adverse events than mefloquine in nonimmune individuals. Significantly fewer recipients of atovaquone/proguanil discontinued treatment because of adverse events than individuals receiving chloroquine plus proguanil or mefloquine (p < 0.05). Conclusion: Atovaquone/proguanil is a fixed-dose combination antimalarial tablet that provides effective prophylaxis of P. falciparum malaria, including drug-resistant strains. Both atovaquone and proguanil are effective against hepatic stages of P. falciparum, which means that treatment need only continue for 7 days after leaving a malaria-endemic region. Atovaquone/proguanil was generally well tolerated and was associated with fewer gastrointestinal adverse events than chloroquine plus proguanil, and fewer neuropsychiatric adverse events than mefloquine. Thus, atovaquone/proguanil provides effective prophylaxis of P. falciparum malaria and compared with other commonly used antimalarial agents has an improved tolerability profile, and, overall, a more convenient dosage regimen, particularly in the post-travel period. Atovaquone, a hydroxynaphthoquinone, selectively inhibits parasitic mitochondrial electron transport. Although resistance rapidly develops when atovaquone is used as a single agent against Plasmodium falciparum malaria, in combination with proguanil (a biguanide), its activity is enhanced, thereby reducing the likelihood of the emergence of resistance. Cycloguanil, the primary metabolite of proguanil, acts as a parasite dihydrofolate reductase inhibitor. The enhancement of the atovaquone effect, however, is a result of synergy with proguanil, and although this mechanism is not well understood, it is not thought to involve dihydrofolate reductase inhibition. Both atovaquone and proguanil are active against pre-erythrocytic (hepatic) stages of P. falciparum, thereby providing causal prophylaxis. Both compounds are also active against the erythrocytic parasite stage (suppressive prophylaxis). Atovaquone was more active against various clones and isolates of P. falciparum in the erythrocytic stage than other antimalarial drugs in in vitro studies. The mean 50% inhibitory plasma concentrations (IC₅₀) of atovaquone (0.7–4.3 nmol/L) were lower than those of chloroquine, quinine, mefloquine and artemether against various isolates of P. falciparum. Atovaquone showed similar activity against both chloroquine-sensitive and -resistant isolates of P. falciparum. Atovaquone/proguanil 250/100mg once daily demonstrated effective causal prophylaxis of P. falciparum malaria in a double-blind, placebo-controlled study in healthy volunteers (n = 16). Parasitaemia was eliminated in all volunteers who received 8 days’ prophylaxis with atovaquone/proguanil and, on day 2, were challenged with bites from mosquitoes infected with P. falciparum malaria; i.e. parasitaemia was eliminated before erythrocytic-stage infection developed. All placebo recipients (n = 4) developed parasitaemia. Cross-resistance between atovaquone and other antimalarial agents has not been observed in vitro or in malaria rodent models, possibly due to different target sites. There were no clinically relevant effects on the pharmacokinetic profiles of atovaquone, proguanil or cycloguanil after oral administration of single or multiple doses of a fixed combination tablet of atovaquone/proguanil 250/100mg once daily for 13 days. Atovaquone is highly lipophilic with low aqueous solubility and shows linear pharmacokinetics, when...