2015 - Hersonissos, Crete - Greece

PAGE 2015: Targeting Ebola
France Mentré

Estimating an effective dose for a repurposed drug to treat Ebola: the case of favipiravir

France Mentré (1), Anne-Marie Taburet (2), Jeremie Guedj (1), Naïm Bouazza (3), Jean-Marc Treluyer (3,4),Xavier Anglaret (5), Sakoba Keïta (6), Xavier de Lamballerie (7), Pierre Frange (8), Denis Malvy (5)

(1) INSERM, IAME, UMR 1137, F-75018 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France, (2) Assistance-Publique Hôpitaux de Paris, Hôpital Bicêtre, Univ Paris-Sud; INSERM U1012; DHU Hepatinov, Kremlin Bicêtre, France, (3) Unité de Recherche Clinique, Assistance Publique – Hôpitaux de Paris (AP-HP), Hôpital Tarnier, Paris, France; EA08, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, (4) Service de Pharmacologie clinique, AP-HP, Groupe hospitalier Paris Centre, Hôpital Cochin, Paris, France; CIC-0901 INSERM, Cochin-Necker, Paris, France, (5) UMR 897, INSERM, F-33076 Bordeaux, France, (6) Ministry of Health, Guinea, (7) UMR_D 190, Aix-Marseille Univ, Institut de Recherche pour le Développement, F-13005 Marseille, France, (8) Laboratoire de Microbiologie, AP-HP, Hôpital Necker – Enfants malades, Paris, France; EA 7327, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Objectives: Although several antivirals demonstrated an effect against Ebola Virus (EBOV) in vitro or in animal models, none of them were evaluated in humans with Ebola Virus Disease (EVD) when the outbreak started. Potential drug candidates included favipiravir [1], a nucleotide analog approved for novel or re-emerging influenza in Japan. Two studies in EBOV infected mice showed that the initiation of favipiravir within 6 days of infection induced a rapid virus clearance, and led to 100% survival [2,3]. Moreover favipiravir showed a good safety profile in thousands of patients worldwide, was immediately available and can be used orally. The objective of this work was to propose a dosage regimen of favipiravir in adults and in children for the JIKI trial conducted in Guinea.

Methods: Our approach combined data on favipiravir efficacy against EBOV in vitro and in vivo with data provided by the manufacturer on favipiravir pharmacokinetics in uninfected mice and humans. First we used the dosage regimen in successfully treated mice to estimate plasma favipiravir concentrations to be targeted in humans. Second we used the pharmacokinetic model developed by the manufacturer in humans with the parameters values estimated in US healthy volunteers to evaluate dosage regimen that could achieve these targeted concentrations in adults. Simulations were performed with various loading and maintenance doses. For children, there was no clinical experience about favipiravir. Maturation profiles of enzymes (mainly aldehyde oxydase) involved in the metabolic pathway of favipiravir are fully achieved at the age of 12 months [4,5]. Therefore, the same population PK model was used to predict the disposition in pediatric patients, over one year, using weight-based allometric scaling [6].

Results: The proposed regimen of favipiravir in adults was a loading dose of 2400/2400 /1200 mg every eight hours on day 1, and a maintenance dose of 1200 mg bid afterwards [7]. This dosage regimen is 50% greater than the one in the Phase 3 trials of favipiravir for influenza in US. To limit the chance of relapse in EVD, we decided to give the treatment for 10 days, which corresponds to the time needed for an effective antibody response [8]. For children over on year, a weight-band dosing table was defined [9].

Conclusions: Modelling was used to define the first dosage regimen of favipiravir in in adults and children with EVD. Tolerance, virological and pharmacokinetic data are collected in the JIKI trial and their analysis will help refining the dosage regimen.

[1] Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013; 100: 446-54.
[2] Smither SJ, Eastaugh LS, Steward JA, Nelson M, Lenk RP, Lever MS. Post-exposure efficacy of Oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Res. 2014; 104: 153-5.
[3] Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 2014; 105: 17-21.
[4] Tayama Y, Miyake K, Sugihara K, et al. Developmental changes of aldehyde oxidase activity in young Japanese children. Clin Pharmacol Ther, 2007; 81: 567-72.
[5] Tayama Y, Sugihara K, Sanoh S, Miyake K, Kitamura S, Ohta S. Developmental changes of aldehyde oxidase activity and protein expression in human liver cytosol. Drug Metab Pharmacokinet, 2012; 27: 543-7.
[6] Anderson BJ, Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol, 2008; 48: 303-332
[7] Mentré F, Taburet AM, Guedj J, Anglaret X, Keîta S, de Lamballerie X, Malvy D. Choice of dosage regimen for the first evaluation of faripiravir in humans infected with Ebola virus. Lancet Infect Dis, 2015; 15:150-1 [8] Ksiazek T, Rollin P, Williams A, et al. Clinical virology of Ebola hemorrhagic fever (EHF): virus, virus antigen, and IgG and IgM antibody findings among EHF patients in Kikwit, Democratic Republic of the Congo, 1995. J Infect Dis. 1999; 179: S177-87.
[9] Bouazza N, Treluyer JM, Foissac F, Mentré F, Taburet AM, Guedj J, Anglaret X, de Lamballerie X, Keïta S, Malvy D, Frange P. Favipiravir for children with Ebola. Lancet, 2015, 385:603-4.

Reference: PAGE 24 (2015) Abstr 3673 [www.page-meeting.org/?abstract=3673]
Oral: Targeting Ebola
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