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Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted

By Thi Huyen Tram Nguyen, Jérémie Guedj, Xavier Anglaret, Cédric Laouénan, Vincent Madelain, Anne-Marie Taburet, Sylvain Baize, Daouda Sissoko, Boris Pastorino, Anne Rodallec, Géraldine Piorkowski, Sara Carazo, Mamoudou Conde, Jean-Luc Gala, Joseph Akoi Bore, Caroline Carbonnelle, Frédéric Jacquot, Hervé Raoul, Denis Malvy, Xavier De Lamballerie and France Mentré

Abstract

International audiencen 2014–2015, the JIKI trial was conducted in Guinea to test favipiravir tolerance and efficacy in patients with Ebola virus disease (EDV). The main results of the trial were previously published without drug concentrations which were not available at the time of publication. The purpose of this study was to report favipiravir concentrations achieved in participants in the JIKI trial and to compare them with the targeted concentrations. We analyzed drug concentrations obtained at Day-2 and Day-4 and compared them to the targeted concentrations. At Day-2, favipiravir concentrations were significantly below but still close to the targeted concentration. At Day-4, a significant and unanticipated drop of concentrations as compared to Day-2 was observed. The origin of the lower-than-targeted concentrations and the unexpected drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. No significant correlation was found between the drug exposure and the virological response, indicating that it is possible that the favipiravir concentrations in the JIKI trial were not sufficient to strongly inhibit the viral replication. These findings suggest the necessity of performing dose-ranging studies with high doses of favipiravir in healthy volunteers to inform any further development of favipiravir for treatment of EVD

Topics: Pharmacokinetics, Viral load, Hematology, Albumins, Dose prediction methods, Blood plasma, Drug therapy, Creatinine, MESH: Adolescent, MESH: Adult, MESH: Child, Preschool, MESH: Ebolavirus, MESH: Female, MESH: Guinea, MESH: Hemorrhagic Fever, Ebola, MESH: Humans, MESH: Male, MESH: Middle Aged, MESH: Pyrazines, MESH: Young Adult, MESH: Aged, MESH: Amides, MESH: Antiviral Agents, MESH: Child, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
Publisher: 'Public Library of Science (PLoS)'
Year: 2017
DOI identifier: 10.1371/journal.pntd.0005389
OAI identifier: oai:HAL:hal-02309055v1
Provided by: HAL-Paris 13
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