Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.: Favipiravir pharmacokinetics in non-human primates

Vincent Madelain 1, * Jérémie Guedj 1 France Mentré 1 Thi Huyen Tram Nguyen 1 Frédéric Jacquot 2 Lisa Oestereich 3, 4 Takumi Kadota 5 Koichi Yamada 5 Anne-Marie Taburet 6 Xavier De Lamballerie 7 Hervé Raoul 2
* Auteur correspondant
1 IAME - Infection, Antimicrobiens, Modélisation, Evolution
2 Unité de service 3 - Laboratoire P4 Jean Mérieux-Inserm [Lyon]
3 DZIF - German Centre for Infection Research [Hamburg, Germany]
4 Department of Virology [Hamburg, Germany]
5 Toyama chemicals laboratory [Toyama, Japan]
6 IMVA - U1184 - Immunologie des Maladies Virales et Autoimmunes
7 EPV - Emergence des Pathologies Virales
Abstract : Favipiravir is a RNA polymerase inhibitor that showed a 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 non-human primates (NHP) 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 BID. A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens and the model predictions were compared to the EC50 of favipiravir against several viruses. Favipiravir pharmacokinetics was described by a model accounting for concentration dependent aldehyde oxidase inhibition. The enzyme dependent elimination rate increased over time and was higher in NHPs from Mauritian than from Chinese origin. Maintenance dose of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above EC50 of Lassa and Marburg virus until day 7. For Ebola virus higher doses are required. After day 7, a 20% dose increase is needed to compensate the increase in drug clearance over time. These results will help rationalize the choice of the dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.
Keywords : Favipiravir Modeling Pharmacokinetics Non human primate Haemorrhagic fevers
Type de document :
Article dans une revue
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2016, January 2017, 61 (1), pp.e01305-16. 〈http://aac.asm.org/content/61/1/e01305-16〉. 〈10.1128/AAC.01305-16〉
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Vincent Madelain, Jérémie Guedj, France Mentré, Thi Huyen Tram Nguyen, Frédéric Jacquot, et al.. Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.: Favipiravir pharmacokinetics in non-human primates. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2016, January 2017, 61 (1), pp.e01305-16. 〈http://aac.asm.org/content/61/1/e01305-16〉. 〈10.1128/AAC.01305-16〉. 〈inserm-01524308〉

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