title: The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria.
abstract: OBJECTIVE
  To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil.
  
  
  METHODS
  Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily.
  
  
  RESULTS
  The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (+/- SEM) oral clearance (Cl/F) estimates were 313+/-33 ml/h/kg and 1109+/-43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0+/-1.3 l/kg and 22.9+/-1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria.
  
  
  CONCLUSIONS
  Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.
authors.affiliation: Shoklo Malaria Research Unit, PO Box 46, Mae Sot, Thailand.
authors.forename: R
authors.initials: R
authors.lastname: McGready
authors.forename: K
authors.initials: K
authors.lastname: Stepniewska
authors.forename: M D
authors.initials: MD
authors.lastname: Edstein
authors.forename: T
authors.initials: T
authors.lastname: Cho
authors.forename: G
authors.initials: G
authors.lastname: Gilveray
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: D000208:Acute Disease; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077332:Artesunate; D053626:Atovaquone; D004338:Drug Combinations; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D009285:Naphthoquinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D011256:Pregnancy Outcome; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D002727:Proguanil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D013785:Thailand
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D009285:Naphthoquinones; D012717:Sesquiterpenes; D000077332:Artesunate; D002727:Proguanil; D053626:Atovaquone