title: Absence of an interaction between artesunate and atovaquone--proguanil.
abstract: OBJECTIVE
  Atovaquone plus proguanil is a new, well-tolerated and highly effective antimalarial drug. In order to protect it from the development of resistance, it may be deployed in combination with an artemisinin derivative. To investigate whether artesunate affects the pharmacokinetics of atovaquone plus proguanil, and to provide preliminary information regarding the tolerability of the triple drug combination (artesunate plus atovaquone plus proguanil), a cross over study was conducted in adult volunteers.
  
  
  METHODS
  Twelve healthy Karen adults were randomised to receive atovaquone-proguanil (1000/400 mg) with or without artesunate (250 mg) and, at least 90 days later, the study was repeated. Blood was sampled over a 10-day period.
  
  
  RESULTS
  The three-drug combination was well tolerated. Artesunate did not alter the pharmacokinetic properties of atovaquone and proguanil (maximum plasma concentrations: 13.02 microg/ml and 742 ng/ml; elimination half-lives: 42.2 h and 14.4 h; oral plasma clearance estimates: 90 ml/h/kg and 710 ml/h/kg; and apparent volumes of distribution: 4.9 1/kg and 14.5 1/kg, respectively). There was also no effect of artesunate on the biotransformation of proguanil to cycloguanil. The pharmacokinetic variables were similar to those reported previously for the individual drugs.
  
  
  CONCLUSIONS
  Artesunate does not influence atovaquone or proguanil pharmacokinetics. The triple-drug combination of atovaquone and proguanil and artesunate was well tolerated.
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand.
authors.forename: M
authors.initials: M
authors.lastname: van Vugt
authors.forename: M D
authors.initials: MD
authors.lastname: Edstein
authors.forename: S
authors.initials: S
authors.lastname: Proux
authors.forename: K
authors.initials: K
authors.lastname: Lay
authors.forename: M
authors.initials: M
authors.lastname: Ooh
authors.forename: S
authors.initials: S
authors.lastname: Looareesuwan
authors.forename: N J
authors.initials: NJ
authors.lastname: White
authors.forename: F
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D037621:Artemisinins; D000077332:Artesunate; D053626:Atovaquone; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D002727:Proguanil / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D012717:Sesquiterpenes / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D009285:Naphthoquinones; D012717:Sesquiterpenes; D000077332:Artesunate; D002727:Proguanil; D053626:Atovaquone