title: Atovaquone and proguanil hydrochloride: a review of nonclinical studies.
abstract: BACKGROUND
  Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hydrochloride is a new antimalarial drug combination that has recently become available in many countries.
  
  
  METHODS
  Data were reviewed from nonclinical studies evaluating the microbiology, secondary pharmacology, pharmacokinetics, and toxicology of atovaquone and proguanil hydrochloride.
  
  
  RESULTS
  Atovaquone is highly active against asexual erythrocytic stages of Plasmodium falciparum in vitro (IC50 0.7-6 nM) and in animal models. Proguanil per se has only weak antimalarial activity in vitro (IC50 2.4-19 microM), 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-erythrocytic (hepatic) stages of malaria parasites. Atovaquone is a ubiquinone antagonist that inhibits mitochondrial electron transport and collapses mitochondrial membrane potential. The proguanil metabolite cycloguanil is a dihydrofolate reductase inhibitor, but the mode of action of proguanil is unknown. In screening evaluations of secondary pharmacology, neither atovaquone nor proguanil had activity that adversely affected gastrointestinal, cardiovascular, or central or autonomic nervous system functions at clinically relevant concentrations. After oral administration, atovaquone exposure is extensive in rats but limited in dogs, while proguanil and cycloguanil exposure is extensive in dogs but limited in rats. In both species, toxicity was related to proguanil exposure, the principal manifestations being salivation, emesis, and loss of body weight. Neither atovaquone nor proguanil was teratogenic or mutagenic. An increased incidence of hepatic adenomas and adenocarcinomas was seen in mice, but not rats, after lifetime exposure to atovaquone, and appears to be related to species-specific differences in hepatic enzymatic activity. No additional toxicity was evident in animals treated with the combination of atovaquone and proguanil hydrochloride compared to those treated with either drug alone.
  
  
  CONCLUSIONS
  Nonclinical studies of atovaquone and proguanil hydrochloride supported the clinical development of this combination for treatment and prophylaxis of malaria.
authors.affiliation: Systems Biology Unit, Glaxo Wellcome Research & Development, Medicines Research Centre, Stevenage, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pudney
authors.forename: W
authors.initials: W
authors.lastname: Gutteridge
authors.forename: A
authors.initials: A
authors.lastname: Zeman
authors.forename: M
authors.initials: M
authors.lastname: Dickins
authors.forename: J L
authors.initials: JL
authors.lastname: Woolley
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D053626:Atovaquone / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018890:Chemoprevention / Q000379:methods; D004196:Disease Outbreaks / Q000517:prevention & control; D004285:Dogs; D004338:Drug Combinations; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D023421:Models, Animal; D010963:Plasmodium falciparum / Q000187:drug effects; D010965:Plasmodium malariae / Q000187:drug effects*; D002727:Proguanil / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D014195:Travel
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C109496:atovaquone, proguanil drug combination; D002727:Proguanil; D053626:Atovaquone