title: Lack of a pharmacokinetic interaction between atovaquone and proguanil.
abstract: OBJECTIVE
  To assess the magnitude of the putative effect of atovaquone on the pharmacokinetics of proguanil and to determine whether the pharmacokinetics of atovaquone are affected by concomitant administration of proguanil, with both drugs administered for 3 days to healthy adult volunteers.
  
  
  METHODS
  This was an open-label, randomized, three-way cross-over study, in which 18 healthy volunteers received 400 mg proguanil, 1000 mg atovaquone and 1000 mg atovaquone + 400 mg proguanil. Each treatment was given once daily for 3 days with a 3-week wash-out period between each occasion. For the assay of proguanil, cycloguanil and atovaquone, blood was sampled before dosing and at regular intervals over 8 days when proguanil was given, and over 17 days when atovaquone was given.
  
  
  RESULTS
  The geometric mean of the area under the atovaquone plasma concentration-time curve calculated from 0 to 24 h after the last dose (AUC0->24h) was 180 microg x ml(-1) h following administration of atovaquone alone and 193 microg x ml(-1) h following atovaquone with proguanil. The geometric mean AUC0->24h for proguanil was 6296 ng x ml(-1) x h after proguanil alone and 5819 ng x ml(-1) x h following proguanil with atovaquone. The corresponding values for the metabolite cycloguanil were 1297 ng x ml(-1) x h and 1187 ng x ml(-1) x h, respectively. The geometric mean elimination half-life (t1/2) of atovaquone was 57.1 h when given alone and 59.0 h when administered together with proguanil. The corresponding geometric mean values of t1/2 for proguanil were 13.7 h and 14.5 h. Exploratory statistical analysis showed no important gender effects on the pharmacokinetics of atovaquone, proguanil, or cycloguanil.
  
  
  CONCLUSIONS
  The pharmacokinetics of atovaquone and proguanil and its metabolite, cycloguanil, were not different when atovaquone and proguanil were given alone or in combination.
authors.affiliation: Laboratoire Glaxo Wellcome, Pharmacologie Clinique, Marly-le-Roi, France. cg33250@glaxowellcome.co.uk
authors.forename: C
authors.initials: C
authors.lastname: Gillotin
authors.forename: J P
authors.initials: JP
authors.lastname: Mamet
authors.forename: L
authors.initials: L
authors.lastname: Veronese
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053626:Atovaquone; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D009285:Naphthoquinones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002727:Proguanil / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012737:Sex Factors; D014227:Triazines / Q000097:blood
chemical_list: D000962:Antimalarials; D009285:Naphthoquinones; D014227:Triazines; C026009:cycloguanil; D002727:Proguanil; D053626:Atovaquone