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.
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Authors | Gregory A Deye, R Scott Miller, Lori Miller, Carola J Salas, Donna Tosh, Louis Macareo, Bryan L Smith, Susan Fracisco, Emily G Clemens, Jittawadee Murphy, Jason C Sousa, J Stephen Dumler, Alan J Magill |
Journal | Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
(Clin Infect Dis)
Vol. 54
Issue 2
Pg. 232-9
(Jan 15 2012)
ISSN: 1537-6591 [Electronic] United States |
PMID | 22052893
(Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Antimalarials
- Drug Combinations
- Placebos
- Proguanil
- Atovaquone
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Topics |
- Adult
- Antimalarials
(administration & dosage, adverse effects, pharmacokinetics)
- Area Under Curve
- Atovaquone
(administration & dosage, adverse effects, pharmacokinetics)
- Chemoprevention
(methods)
- Cohort Studies
- Drug Combinations
- Female
- Humans
- Malaria, Falciparum
(drug therapy, metabolism, prevention & control)
- Male
- Middle Aged
- Parasitemia
(drug therapy, metabolism, prevention & control)
- Placebos
- Plasmodium falciparum
(drug effects)
- Proguanil
(administration & dosage, adverse effects, pharmacokinetics)
- Sporozoites
(drug effects)
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