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Title
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Chemoprotective antimalarial activity of P218 against Plasmodium falciparum : a randomized, placebo-controlled volunteer infection study
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Author
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Abstract
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| P218 is a highly selective dihydrofolate reductase inhibitor with potent in vitro activity against pyrimethamineresistant Plasmodium falciparum. This single-center, randomized, double-blind, placebo-controlled phase Ib study evaluated P218 safety, pharmacokinetics, and chemoprotective efficacy in a P. falciparum sporozoite (PfSPZ) volunteer infection study (VIS). Consecutive dose safety and tolerability were evaluated (cohort 1), with participants receiving two oral doses of P218 1,000 mg 48 hours apart (n = 6), or placebo (n = 2). P218 chemoprotective efficacy was assessed (cohorts 2 and 3) with direct venous inoculation of 3,200 aseptic, cryopreserved PfSPZ (NF54 strain) followed 2 hours later with two P218 doses of 1,000 mg (cohort 2, n = 9) or 100 mg (cohort 3, n = 9) administered 48 hours apart, or placebo (n = 6). Parasitemia was assessed from day 7 using quantitative PCR targeting the var gene acidic terminal sequence (varATS qPCR). By day 28, all participants in cohort 2 (P218 1,000 mg) and 8/9 in cohort 3 (P218 100 mg) were sterilely protected post-PfSPZ VIS, confirming P218 P. falciparum chemoprotective activity. With placebo, all six participants became parasitemic (geometric mean time to positive parasitemia 10.6 days [90% CI: 9.9-11.4]). P218 pharmacokinetics were similar in participants with or without induced infection. Adverse events of any cause occurred in 45.8% (11/24) of participants who received P218 and 50.0% (4/8) following placebo; all were mild/moderate in severity, transient, and self-limiting. There were no clinically relevant changes in laboratory parameters, vital signs, or electrocardiograms. P218 displayed excellent chemoprotective efficacy against P. falciparum with favorable safety and tolerability. |
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Language
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English
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Source (journal)
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The American journal of tropical medicine and hygiene. - Baltimore, Md
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Publication
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Baltimore, Md
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2021
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ISSN
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0002-9637
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DOI
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10.4269/AJTMH.20-1165
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Volume/pages
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104
:4
(2021)
, p. 1348-1358
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ISI
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000651202000030
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Pubmed ID
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33556040
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Full text (Publisher's DOI)
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Full text (open access)
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