Vincent Madelain (1), Jérémie Guedj (1), France Mentré (1), Thi Huyen Tram Nguyen (1), Koichi Yamada (2), Yousuke Furuta (2), Takumi Kadota (2), Anne-Marie Taburet (3), Frédéric Jacquot (4), Xavier de Lamballerie (5,6), Hervé Raoul (4)
(1) INSERM, IAME, UMR 1137, F-75018 Paris, France ; Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France (2) Dept.,Research Laboratory of Toyama Chemical Co., Ltd, Japan (3) Hospital Bicêtre, Assistance Publique-Hôpitaux de Paris, DHU Hepatinov ; INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Kremlin Bicêtre, France (4) Laboratoire P4 Inserm-Jean Mérieux, US003 Inserm, 69365 Lyon, France (5) Aix Marseille Université, IRD French Institute of Research for Development, EHESP French School of Public Health, EPV UMR_D 190
Objectives: Favipiravir is an antiviral nucleotide analogue with exhibited antiviral effectiveness against several hemorrhagic fever viruses in small animals [1–3], but its efficacy in non-human primates (NHPs) has not been assessed. Here, in order to prepare efficacy studies, we characterize for the first time the pharmacokinetics (PK) of favipiravir administered intravenously for up to 2 weeks.
Methods: PK studies of favipiravir in Cynomolgus macaques from Chinese and Mauritian origin were performed in Japan and France, respectively. Favipiravir was given up to 14 days, with a loading dose of 200-250 mg/kg BID at day 1 followed by a maintenance dose of 60, 100 or 150 mg/kg BID (Chinese NHPs) and 100, 150 or 180 mg/kg BID (Mauritian NHPs). Following a population approach, a PK model was developed to estimate the effect of dose, sex, breed, and to predict by simulation the exposure achieved in various dosing regimen. Assuming a protein binding rate of 50% [4], we proposed doses of favipiravir needed to achieve free concentrations close or above EC50 values reported for Ebola virus (50 µg/L [5]), Rift Valley fever and Lassa viruses (5 µg/L [1,3]) and for Crimea-Congo virus (1 µg/L [6]).
Results: No serious abnormality in the 30 NHPs studied was observed at any of the doses tested. PK was highly non-linear over doses and time with a 20-50% reduction in average concentration at day 14 compared to day 7. This non-linearity was explained in the model by a time-dependent elimination mediated by aldehyde oxidase, the main enzyme involved in favipiravir metabolism [7]. The clearance rate was also affected by breed, with concentrations much lower in Mauritian than in Chinese NHPs. Consequently doses of 150 and 130 mg/kg BID in NHPs of Mauritian and Chinese origin, respectively, may be needed to maintain concentration above or close to favipiravir’s EC50 against EBOV until day 14. Lower maintenance doses of 130 and 100 mg/kg BID in NHPs of Mauritian and Chinese origin, respectively, should be sufficient for Rift valley fever, Lassa and Crimea-Congo viruses.
Conclusions: Our results shows that favipiravir PK was largely nonlinear over doses and time, leading to a large decrease in concentrations after day 7, that could be captured by a mechanistic enzyme based model. In absence of intracellular data, dose recommendation was based on protein unbound plasma concentrations, but the relevance of this approach will need further efficacy studies.
References:
[1] Oestereich L, Rieger T, Lüdtke A, Ruibal P, Wurr S, Pallasch E, et al. Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever. J. Infect. Dis. 2015;
[2] 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.
[3] Gowen BB, Wong M-H, Jung K-H, Sanders AB, Mendenhall M, Bailey KW, et al. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob. Agents Chemother. 2007;51:3168–76.
[4] Mentré F, Taburet A-M, Guedj J, Anglaret X, Keïta S, de Lamballerie X, et al. Dose regimen of favipiravir for Ebola virus disease. Lancet Infect. Dis. 2015;15:150–1.
[5] 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.
[6] Oestereich L, Rieger T, Neumann M, Bernreuther C, Lehmann M, Krasemann S, et al. Evaluation of antiviral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for Crimean-Congo hemorrhagic fever. PLoS Negl. Trop. Dis. 2014;8:e2804.
[7] Madelain V, Nguyen THT, Olivo A, de Lamballerie X, Guedj J, Taburet A-M, et al. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Clin. Pharmacokinet. 2016; in press
Reference: PAGE 25 (2016) Abstr 5716 [www.page-meeting.org/?abstract=5716]
Poster: Drug/Disease modeling - Infection