title: Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.
abstract: Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC50) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC50for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France vincent.madelain@inserm.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Madelain
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Guedj
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Mentré
authors.affiliation: IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Thi Huyen Tram
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Laboratoire P4 INSERM-Jean Mérieux, US003 INSERM, Lyon, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jacquot
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.|German Center for Infection Research (DZIF), Partner Site, Hamburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Oestereich
authors.affiliation: Department of Research Laboratory of Toyama Chemical Co., Ltd., Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kadota
authors.affiliation: Department of Research Laboratory of Toyama Chemical Co., Ltd., Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Hopital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, CEA, Université Paris-Sud, Kremlin Bicêtre, Paris, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
authors.affiliation: UMR Emergence des Pathologies Virales (Aix-Marseille University-IRD 190-INSERM 1207-EHESP), Marseille, France.|Institut Hospitalo-Universitaire Méditerranée Infection, Marseille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: de Lamballerie
authors.affiliation: Laboratoire P4 INSERM-Jean Mérieux, US003 INSERM, Lyon, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Raoul
mesh_terms: D061605:Administration, Intravenous; D042931:Aldehyde Oxidase / Q000378:metabolism; D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000187:drug effects / Q000472:pathogenicity; D006482:Hemorrhagic Fevers, Viral / Q000188:drug therapy* / Q000821:virology; D011323:Primates; D011719:Pyrazines / Q000627:therapeutic use*; D014709:Vero Cells
chemical_list: D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D042931:Aldehyde Oxidase; C462182:favipiravir
keywords: favipiravir; hemorrhagic fever; modelling; nonhuman primates; population pharmacokinetics