title: Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted.
abstract: In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations.
  
  
  
  Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient's individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient's characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10-6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality.
  
  
  
  Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses.
  
  
  
  ClinicalTrials.gov NCT02329054.
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France; Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: Thi Huyen Tram
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France; Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.
authors.forename: Jérémie
authors.identifier: 0000-0002-5534-5482
authors.initials: J
authors.lastname: Guedj
authors.affiliation: Inserm, UMR 1219, Université de Bordeaux, Bordeaux, France.|Programme PACCI/site ANRS de Côte d'Ivoire, Abidjan, Côte d'Ivoire.
authors.forename: Xavier
authors.initials: X
authors.lastname: Anglaret
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France; Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Bichat Claude Bernard, Paris, France.
authors.forename: Cédric
authors.identifier: 0000-0002-3681-6314
authors.initials: C
authors.lastname: Laouénan
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France; Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Bichat Claude Bernard, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Madelain
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Paris, France and Inserm UMR1184, Université Paris-Sud.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
authors.affiliation: UBIVE, Institut Pasteur, Centre International de Recherche en Infectiologie, Lyon, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baize
authors.affiliation: Inserm, UMR 1219, Université de Bordeaux, Bordeaux, France.|Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Daouda
authors.identifier: 0000-0002-8890-7170
authors.initials: D
authors.lastname: Sissoko
authors.affiliation: Université Aix Marseille, Institut de Recherche pour le Développement, École des Hautes Études en Santé Publique, EPV, Marseille, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Pastorino
authors.affiliation: Université Aix Marseille, Institut de Recherche pour le Développement, École des Hautes Études en Santé Publique, EPV, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rodallec
authors.affiliation: Université Aix Marseille, Institut de Recherche pour le Développement, École des Hautes Études en Santé Publique, EPV, Marseille, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Piorkowski
authors.affiliation: Médecins Sans Frontières Belgique, Brussels, Belgium.
authors.forename: Sara
authors.identifier: 0000-0003-0711-6703
authors.initials: S
authors.lastname: Carazo
authors.affiliation: ALIMA, Dakar, Senegal.
authors.forename: Mamoudou N
authors.initials: MN
authors.lastname: Conde
authors.affiliation: Biological Light Fieldable Laboratory for Emergencies (B-LiFE)/Belgian First Aid and Support (B-FAST), Brussels, Belgium.|Cliniques Universitaires Saint-Luc, Brussels, Belgium.|Université Catholique de Louvain, Louvain-la-Neuve, Belgium.|Belgian Ministry of Defense, Brussels, Belgium.
authors.forename: Jean-Luc
authors.identifier: 0000-0002-7749-573X
authors.initials: JL
authors.lastname: Gala
authors.affiliation: European Mobile Laboratory Project, Hamburg, Germany.|Institut National de Santé Publique, Conakry, Guinea.|Laboratoire des Fièvres Hémorragiques en Guinée, Université Gamal Abdel Nasser de Conakry, Conakry, Guinea.
authors.forename: Joseph Akoi
authors.initials: JA
authors.lastname: Bore
authors.affiliation: Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Carbonnelle
authors.affiliation: Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jacquot
authors.affiliation: Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Raoul
authors.affiliation: Inserm, UMR 1219, Université de Bordeaux, Bordeaux, France.|Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Malvy
authors.affiliation: Université Aix Marseille, Institut de Recherche pour le Développement, École des Hautes Études en Santé Publique, EPV, Marseille, France.
authors.forename: Xavier
authors.identifier: 0000-0001-7895-2720
authors.initials: X
authors.lastname: de Lamballerie
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France; Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Bichat Claude Bernard, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Mentré
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D029043:Ebolavirus / Q000187:drug effects / Q000502:physiology; D005260:Female; D016701:Guinea; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; C462182:favipiravir