A Randomized Trial Evaluating the Prophylactic Activity of DSM265 Against Preerythrocytic Plasmodium falciparum Infection During Controlled Human Malarial Infection by Mosquito Bites and Direct Venous Inoculation.

Autor:	Murphy SC; Department of Laboratory Medicine, University of Washington, Seattle, Washington.; Department of Microbiology, University of Washington, Seattle, Washington.; Center for Emerging and Re-emerging Infectious Diseases, Seattle, Washington.; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Human Challenge Center, Center for Infectious Disease Research, Seattle, Washington., Duke ER; Department of Medicine, University of Washington, Seattle, Washington.; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington., Shipman KJ; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Jensen RL; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Fong Y; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Ferguson S; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Janes HE; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Gillespie K; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Seilie AM; Department of Laboratory Medicine, University of Washington, Seattle, Washington., Hanron AE; Department of Laboratory Medicine, University of Washington, Seattle, Washington., Rinn L; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington., Fishbaugher M; Human Challenge Center, Center for Infectious Disease Research, Seattle, Washington., VonGoedert T; Human Challenge Center, Center for Infectious Disease Research, Seattle, Washington., Fritzen E; Human Challenge Center, Center for Infectious Disease Research, Seattle, Washington., Kappe SH; Human Challenge Center, Center for Infectious Disease Research, Seattle, Washington., Chang M; Department of Laboratory Medicine, University of Washington, Seattle, Washington., Sousa JC; Walter Reed Army Institute of Research, Silver Spring, Maryland., Marcsisin SR; Walter Reed Army Institute of Research, Silver Spring, Maryland., Chalon S; Medicines for Malaria Venture, Geneva, Switzerland., Duparc S; Medicines for Malaria Venture, Geneva, Switzerland., Kerr N; Medicines for Malaria Venture, Geneva, Switzerland., Möhrle JJ; Medicines for Malaria Venture, Geneva, Switzerland., Andenmatten N; Medicines for Malaria Venture, Geneva, Switzerland., Rueckle T; Medicines for Malaria Venture, Geneva, Switzerland., Kublin JG; Department of Global Health, University of Washington, Seattle, Washington.; Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Jazyk:	angličtina
Zdroj:	The Journal of infectious diseases [J Infect Dis] 2018 Feb 14; Vol. 217 (5), pp. 693-702.
DOI:	10.1093/infdis/jix613
Abstrakt:	Background: DSM265 is a selective inhibitor of Plasmodium dihydroorotate dehydrogenase that fully protected against controlled human malarial infection (CHMI) by direct venous inoculation of Plasmodium falciparum sporozoites when administered 1 day before challenge and provided partial protection when administered 7 days before challenge. Methods: A double-blinded, randomized, placebo-controlled trial was performed to assess safety, tolerability, pharmacokinetics, and efficacy of 1 oral dose of 400 mg of DSM265 before CHMI. Three cohorts were studied, with DSM265 administered 3 or 7 days before direct venous inoculation of sporozoites or 7 days before 5 bites from infected mosquitoes. Results: DSM265-related adverse events consisted of mild-to-moderate headache and gastrointestinal symptoms. DSM265 concentrations were consistent with pharmacokinetic models (mean area under the curve extrapolated to infinity, 1707 µg*h/mL). Placebo-treated participants became positive by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and were treated 7-10 days after CHMI. Among DSM265-treated subjects, 2 of 6 in each cohort were sterilely protected. DSM265-treated recipients had longer times to development of parasitemia than placebo-treated participants (P < .004). Conclusions: This was the first CHMI study of a novel antimalarial compound to compare direct venous inoculation of sporozoites and mosquito bites. Times to qRT-PCR positivity and treatment were comparable for both routes. DSM265 given 3 or 7 days before CHMI was safe and well tolerated but sterilely protected only one third of participants. (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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