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 ϭ 17) or Mauritian (n ϭ 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 (EC 50 ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentrationdependent 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 EC 50 for 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.

Zika Virus Replication Is Substantially Inhibited by Novel Favipiravir and Interferon Alpha Combination Regimens

“…In that report, the systemic clearance of FAV was found to be significantly decreased over time. Similar PK properties were also observed in preclinical studies, and these properties were explained by enzyme-mediated elimination with concentration-dependent inhibition (26). Thus, we adapted a previously developed PK model for the autoinhibition of FAV clearance during repeated administration (27).…”

Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019‐nCoV Infection

“…16 Pharmacokinetic analysis of intravenous favipiravir in cynomolgus macaques after repeated doses indicates obvious nonlinear pharmacokinetics over time and over a range of doses, and a continuous decline in plasma concentration after 7 days of continuous administration in the nonhuman primates is also observed. 17 Data obtained from 66 patients for experimental treatment with favipiravir for EVD (named as the JIKI trial) indicated that the steady-state trough concentration notably decreased on day 4 (25.9 µg/mL) as compared with day 2 (46.1 µg/mL), which supports a decrease in drug concentration after continuous use. 18 To further understand the in vivo biodistribution and kinetics of uptake and clearance of favipiravir after a single and repeated administration, an 18 F radiolabeled favipiravir ([ 18 F]favipiravir) was developed.…”

Modeling Favipiravir Antiviral Efficacy Against Emerging Viruses: From Animal Studies to Clinical Trials

“…(horizon 2020 grant 666092) , was set up to evaluate favipiravir efficacy in a context of emergency. The first aim of mathematical modeling was to find the optimal dosing regimen of favipiravir in patients with EVD, for which the drug’s half‐maximal effective concentration (EC 50 ) was much larger than against most strains of influenza virus 8 . The dosing regimen of favipiravir approved in Japanese patients for influenza was 1,600 mg twice daily the first day followed by 600 mg twice daily from the second to the fifth day.…”

“…In the last years, our group was involved in the evaluation of favipiravir, an anti‐influenza drug approved in Japan, that has shown activity against a variety of other RNA viruses, in particular Ebola, Lassa fever, Marburg, Nipah, and Zika viruses 7‐9 . The main advantages of applying an approved agent to treat a new indication, a process called “drug repurposing,” are that the drug is available in large quantities and that safety studies have already been conducted on large populations 10 .…”