First‐in‐human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection
Rattachement africain : ch, au, us, gb. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Aims This first‐in‐human clinical trial of P218, a novel dihydrofolate reductase inhibitor antimalarial candidate, assessed safety, tolerability, pharmacokinetics and food effects in healthy subjects. Methods The study consisted of two parts. Part A was a double‐blind, randomized, placebo‐controlled, parallel group, ascending dose study comprising seven fasted cohorts. Eight subjects/cohort were randomized (3:1) to receive either a single oral dose of P218 (10, 30, 100, 250, 500, 750 and 1000 mg) or placebo. Part B was an open‐label, cross‐over, fed/fasted cohort (eight subjects) that received a 250 mg single dose of P218 in two treatment periods. Results P218 was generally well tolerated across all doses; 21 treatment‐emergent adverse events occurred in 15/64 subjects. Nine adverse events in five subjects, all of mild intensity, were judged drug related. No clinically relevant abnormalities in ECG, vital signs or laboratory tests changes were observed. P218 was rapidly absorbed, with Cmax achieved between 0.5 and 2 hours post dose. Plasma concentrations declined bi‐exponentially with half‐life values ranging from 3.1 to 6.7 hours (10 and 30 mg), increasing up to 8.9 to 19.6 hours (doses up to 1000 mg). Exposure values increased dose‐proportionally between 100 and 1000 mg for P218 (parent) and three primary metabolites (P218 β‐acyl glucuronide, P218‐OH and P218‐OH β‐acyl glucuronide). Co‐administration of P218 with food reduced Cmax by 35% and delayed absorption by 1 hour, with no significant impact on AUC. Conclusion P218 displayed favourable safety, tolerability and pharmacokinetics. In view of its short half‐life, a long‐acting formulation will be needed for malaria chemoprotection.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- First‐in‐human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection
- Date Crossref
- 12/02/2020
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Medicines for Malaria Venture pays non établi dans la noticeOrganisation à but non lucratif
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QIMR Berghofer Medical Research Institute pays non établi dans la noticeStructure de recherche
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PDF Solutions (United States) pays non établi dans la noticeEntreprise
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Loughborough University pays non établi dans la noticeUniversité ou école supérieure
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Richmond Pharmacology Ltd London UK pays non établi dans la noticeEntreprise
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PTx Solutions UK pays non établi dans la noticeInstitution
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Preclinical Safety Consulting Ltd Loughborough Leicestershire UK pays non établi dans la noticeÉtablissement de santé
Medicines for Malaria Venture, QIMR Berghofer Medical Research Institute et PDF Solutions (United States), avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.