{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:32:14Z","timestamp":1790937134279,"version":"4.1.0"},"reference-count":0,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"4","license":[{"start":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T00:00:00Z","timestamp":1617753600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>P218 is a highly selective dihydrofolate reductase inhibitor with potent in vitro activity against pyrimethamine-resistant <jats:italic>Plasmodium falciparum<\/jats:italic>. This single-center, randomized, double-blind, placebo-controlled phase Ib study evaluated P218 safety, pharmacokinetics, and chemoprotective efficacy in a <jats:italic>P. falciparum<\/jats:italic> sporozoite (<jats:italic>Pf<\/jats:italic>SPZ) 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 (<jats:italic>n<\/jats:italic> = 6), or placebo (<jats:italic>n<\/jats:italic> = 2). P218 chemoprotective efficacy was assessed (cohorts 2 and 3) with direct venous inoculation of 3,200 aseptic, cryopreserved <jats:italic>Pf<\/jats:italic>SPZ (NF54 strain) followed 2 hours later with two P218 doses of 1,000 mg (cohort 2, <jats:italic>n<\/jats:italic> = 9) or 100 mg (cohort 3, <jats:italic>n<\/jats:italic> = 9) administered 48 hours apart, or placebo (<jats:italic>n<\/jats:italic> = 6). Parasitemia was assessed from day 7 using quantitative PCR targeting the <jats:italic>var<\/jats:italic> 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-<jats:italic>Pf<\/jats:italic>SPZ VIS, confirming P218 <jats:italic>P. falciparum<\/jats:italic> chemoprotective activity. With placebo, all six participants became parasitemic (geometric mean time to positive parasitemia 10.6 days [90% CI: 9.9\u201311.4]). 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 <jats:italic>P. falciparum<\/jats:italic> with favorable safety and tolerability.<\/jats:p>","DOI":"10.4269\/ajtmh.20-1165","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T15:07:50Z","timestamp":1612796870000},"page":"1348-1358","source":"Crossref","is-referenced-by-count":34,"title":["Chemoprotective Antimalarial Activity of P218 against Plasmodium falciparum: A Randomized, Placebo-Controlled Volunteer Infection Study"],"prefix":"10.4269","volume":"104","author":[{"given":"Mohamed Farouk","family":"Chughlay","sequence":"first","affiliation":[{"name":"1Medicines for Malaria Venture, Geneva, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"El Gaaloul","sequence":"additional","affiliation":[{"name":"1Medicines for Malaria Venture, Geneva, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Donini","sequence":"additional","affiliation":[{"name":"1Medicines for Malaria Venture, Geneva, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Campo","sequence":"additional","affiliation":[{"name":"1Medicines for Malaria Venture, Geneva, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter-Jan","family":"Berghmans","sequence":"additional","affiliation":[{"name":"2SGS Life Sciences, Antwerp, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Lucardie","sequence":"additional","affiliation":[{"name":"2SGS Life Sciences, Antwerp, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Marx","sequence":"additional","affiliation":[{"name":"3ICON Clinical Research GmbH, Langen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed H.","family":"Cherkaoui-Rbati","sequence":"additional","affiliation":[{"name":"1Medicines for Malaria Venture, Geneva, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Langdon","sequence":"additional","affiliation":[{"name":"4PTx Solutions, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u00f1igo","family":"Angulo-Barturen","sequence":"additional","affiliation":[{"name":"5GlaxoSmithKline, Tres Cantos, Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Viera","sequence":"additional","affiliation":[{"name":"5GlaxoSmithKline, Tres Cantos, Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rosanas-Urgell","sequence":"additional","affiliation":[{"name":"6Institute of Tropical Medicine, Antwerp, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Van Geertruyden","sequence":"additional","affiliation":[{"name":"7University of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Chalon","sequence":"additional","affiliation":[{"name":"1Medicines for Malaria Venture, Geneva, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2795","container-title":["The American Journal of Tropical Medicine and Hygiene"],"original-title":[],"link":[{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/104\/4\/article-p1348.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/104\/4\/article-p1348.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T12:30:57Z","timestamp":1617798657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/104\/4\/article-p1348.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,7]]},"references-count":0,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.4269\/ajtmh.20-1165","relation":{},"ISSN":["0002-9637","1476-1645"],"issn-type":[{"value":"0002-9637","type":"print"},{"value":"1476-1645","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,7]]}}}