Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of plasmodium falciparum malaria in a human challenge model

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)232-239
Number of pages8
JournalClinical Infectious Diseases
Volume54
Issue number2
DOIs
StatePublished - Jan 15 2012

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Falciparum Malaria
Chemoprevention
Atovaquone
Proguanil
Volunteers
Plasmodium falciparum
Malaria
Culicidae
proguanil drug combination atovaquone
Placebos
Sporozoites
Parasitemia
Area Under Curve
Half-Life
Microscopy

ASJC Scopus subject areas

  • Infectious Diseases
  • Microbiology (medical)

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Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of plasmodium falciparum malaria in a human challenge model. / Deye, Gregory A.; Miller, R. Scott; Miller, Lori; Salas, Carola J.; Tosh, Donna; MacAreo, Louis; Smith, Bryan L.; Fracisco, Susan; Clemens, Emily G.; Murphy, Jittawadee; Sousa, Jason C.; Dumler, J. Stephen; Magill, Alan J.

In: Clinical Infectious Diseases, Vol. 54, No. 2, 15.01.2012, p. 232-239.

Research output: Contribution to journalArticle

Deye, GA, Miller, RS, Miller, L, Salas, CJ, Tosh, D, MacAreo, L, Smith, BL, Fracisco, S, Clemens, EG, Murphy, J, Sousa, JC, Dumler, JS & Magill, AJ 2012, 'Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of plasmodium falciparum malaria in a human challenge model', Clinical Infectious Diseases, vol. 54, no. 2, pp. 232-239. https://doi.org/10.1093/cid/cir770
Deye, Gregory A. ; Miller, R. Scott ; Miller, Lori ; Salas, Carola J. ; Tosh, Donna ; MacAreo, Louis ; Smith, Bryan L. ; Fracisco, Susan ; Clemens, Emily G. ; Murphy, Jittawadee ; Sousa, Jason C. ; Dumler, J. Stephen ; Magill, Alan J. / Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of plasmodium falciparum malaria in a human challenge model. In: Clinical Infectious Diseases. 2012 ; Vol. 54, No. 2. pp. 232-239.
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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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AU - Miller, R. Scott

AU - Miller, Lori

AU - Salas, Carola J.

AU - Tosh, Donna

AU - MacAreo, Louis

AU - Smith, Bryan L.

AU - Fracisco, Susan

AU - Clemens, Emily G.

AU - Murphy, Jittawadee

AU - Sousa, Jason C.

AU - Dumler, J. Stephen

AU - Magill, Alan J.

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N2 - 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.

AB - 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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