Chemoprotective antimalarial activity of P218 against Plasmodium falciparum : a randomized, placebo-controlled volunteer infection study
| العنوان: | Chemoprotective antimalarial activity of P218 against Plasmodium falciparum : a randomized, placebo-controlled volunteer infection study |
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| المؤلفون: | Brice Campo, Anna Rosanas-Urgell, Mohammed H Cherkaoui-Rbati, Pieter-Jan Berghmans, Myriam El Gaaloul, Alexander Lucardie, Iñigo Angulo-Barturen, Grant Langdon, Sara Viera, M. Farouk Chughlay, Stephan Chalon, Michael W Marx, Jean-Pierre Van Geertruyden, Cristina Donini |
| المصدر: | The American journal of tropical medicine and hygiene The American Journal of Tropical Medicine and Hygiene |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Male, Volunteers, medicine.medical_specialty, Plasmodium falciparum, Mice, Transgenic, Parasitemia, Placebo, Gastroenterology, Cohort Studies, Placebos, Antimalarials, Mice, Random Allocation, Pharmacokinetics, Double-Blind Method, Virology, Internal medicine, medicine, Animals, Humans, Malaria, Falciparum, Volunteer, biology, business.industry, Articles, Middle Aged, medicine.disease, biology.organism_classification, Infectious Diseases, Human Experimentation, Tolerability, Sporozoites, Cohort, Chemoprotective, Folic Acid Antagonists, Parasitology, Female, Human medicine, business |
| الوصف: | P218 is a highly selective dihydrofolate reductase inhibitor with potent in vitro activity against pyrimethamine-resistant 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. |
| اللغة: | English |
| تدمد: | 0002-9637 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::087af19cdf05208b247611f3beace0cf https://repository.uantwerpen.be/docstore/d:irua:6915 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....087af19cdf05208b247611f3beace0cf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00029637 |
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