Atovaquone and proguanil hydrochloride: A review of nonclinical studies

Background: Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hyd rochloride is a new antimalarial drug combination that has recently become available in many countries. Methods: Data were reviewed from nonclinical studies evaluating the microbi ology, secondary pharmacology, pharmacokinetics, and toxicology of atovaquo ne and proguanil hydrochloride. Results: Atovaquone is highly active aga inst asexual erythrocytic stages o f Plasmodium falciparum in vitro (IC50 0.7-6 nM) and in animal models. Prog uanil per se has only weak antimalarial activity in vitro (IC50 2.4-19 mu M ), and its effectiveness depends on the active metabolite cycloguanil (IC50 0.5-2.5 nM). The combination of atovaquone and proguanil is synergistic in vitro. Both drugs also have activity against gametocytes and pre-erythrocy tic (hepatic) stages of mala ria parasites. Atovaquone is a ubiquinone anta gonist that inhibits mitochondrial electron transport and collapses mitocho ndrial membrane potential. The proguanil metabolite cycloguanil is a dihydr ofolate reductase inhibitor, but the mode of action of proguanil is unknown . In screening evaluations of secondary pharmacology, neither atovaquone no r proguanil had activity that adversely affected gastrointestinal, cardiova scular, or central or autonomic nervous system functions at clinically rele vant concentrations. After oral administration, atovaquone exposure is exte nsive in rats but limited in dogs, while proguanil and cycloguanil exposure is extensive in dogs but: limited in rats. In both species, toxicity was r elated to proguanil exposure, the principal manifestations being salivation , emesis, a nd loss of body weight. Neither atovaquone nor proguanil was te ratogen ic or mutagenic. An increased incidence of hepatic adenomas and ade nocarcinomas was seen in mice, but not rats, after lifetime exposure to ato vaquone, and appears to be related to species-specific differences in hepat ic enzymatic activity. No additional toxicity was evident in animals treate d with the combination of atovaquone and proguanil hydrochloride compared t o those treated with either drug alone. Conclusion: Nonclinical studies of atovaquone and proguanil hydrochloride s upported the clinical development of this combination for treatment and pro phylaxis of malaria.