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: 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.)

Chemical References

• Antimalarials
• Drug Combinations
• Placebos
• Proguanil
• Atovaquone

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)