title: Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of Plasmodium falciparum malaria in a human challenge model.
abstract: BACKGROUND
  We conducted a randomized, placebo-controlled, double-blind trial to establish the efficacy of atovaquone-proguanil to prevent malaria with the goal of simulating weekly dosing in a human Plasmodium falciparum challenge model.
  
  
  METHODS
  Thirty volunteers randomly received 1 of the following dose regimens: (1) 250 milligrams of atovaquone and 100 milligrams of proguanil (250/100 milligrams) 1 day prior to infectious mosquito challenge (day -1), (2) 250/100 milligrams on day 4 after challenge, (3) 250/100 milligrams on day -7, (4) 500 milligrams of atovaquone and 200 milligrams of proguanil (500/200 milligrams) on day -7 or, (5) 1000 milligrams of atovaquone and 400 milligrams of proguanil (1000/400 milligrams) on day -7. All regimens included matching placebo such that all volunteers received identical pill numbers. Six volunteers served as open-label infectivity controls. Volunteers underwent mosquito sporozoite challenge with P. falciparum 3D7 strain. Follow-up consisted of serial microscopy and close clinical monitoring for 90 days.
  
  
  RESULTS
  Six of 6 infectivity controls developed parasitemia as expected. Two of 5 evaluable volunteers receiving 250/100 milligrams 7 days prior to challenge and 1 of 6 volunteers receiving 1000/400 milligrams 7 days prior to challenge were microscopically diagnosed with malaria. All other volunteers were protected. Atovaquone exposure (area under the curve) during liver stage development was low in 2 of 3 volunteers with prophylactic failure (423 and 199 ng/mL × days compared with a mean for protected volunteers of 1903 ng/mL × days), as was peak concentration (165 and 81 ng/mL compared with a mean of 594 ng/mL in volunteers with prophylactic success). Elimination half-life was short in volunteers with prophylactic failure (2.4, 2.0, and 3.3 days compared with a mean of 4.1 days in volunteers with prophylactic success).
  
  
  CONCLUSIONS
  Single-dose atovaquone-proguanil provides effective malaria chemoprophylaxis against P. falciparum challenge at dosing intervals supportive of weekly dosing. Postexposure prophylaxis 4 days after challenge was 100% effective.
authors: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring,Maryland 20910, USA. gregory.deye@gmail.com
authors: Gregory A
authors: GA
authors: Deye
authors: R Scott
authors: RS
authors: Miller
authors: Lori
authors: L
authors: Miller
authors: Carola J
authors: CJ
authors: Salas
authors: Donna
authors: D
authors: Tosh
authors: Louis
authors: L
authors: Macareo
authors: Bryan L
authors: BL
authors: Smith
authors: Susan
authors: S
authors: Fracisco
authors: Emily G
authors: EG
authors: Clemens
authors: Jittawadee
authors: J
authors: Murphy
authors: Jason C
authors: JC
authors: Sousa
authors: J Stephen
authors: JS
authors: Dumler
authors: Alan J
authors: AJ
authors: Magill
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D053626:Atovaquone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018890:Chemoprevention / Q000379:methods; D015331:Cohort Studies; D004338:Drug Combinations; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D018512:Parasitemia / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D010919:Placebos; D010963:Plasmodium falciparum / Q000187:drug effects*; D002727:Proguanil / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D034101:Sporozoites / Q000187:drug effects
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D010919:Placebos; D002727:Proguanil; D053626:Atovaquone