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

Abstract

on behalf of the Reaction! Research GroupIn 2014, our research network was involved in the evaluation of favipiravir, an anti-influenza polymerase inhibitor, against Ebola virus. In this review, we discuss how mathematical modeling was used, first to propose a relevant dosing regimen in humans, and then to optimize its antiviral efficacy in a nonhuman primate (NHP) model. The data collected in NHPs were finally used to develop a model of Ebola pathogenesis integrating the interactions among the virus, the innate and adaptive immune response, and the action of favipiravir. We conclude the review of this work by discussing how these results are of relevance for future human studies in the context of Ebola virus, but also for other emerging viral diseases for which no therapeutics are available.

Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model

“…Favipiravir undergoes an important hepatic metabolism mainly by aldehyde oxidase producing an inactive M1 metabolite and inhibits aldehyde oxidase activity in a concentration-and time-dependent manner. These properties explain the self-inhibition of its own metabolism as observed in our study in which the highest dose of favipiravir led to a greater increase in favipiravir concentrations 38 .…”

“…Accumulation ratios were respectively 6, 16 and at the doses, confirming the non-proportional increase between doses. The average concentration after single dose administration over 0 to 12-hour intervals was calculated and the respective values obtained were 10.1µg/mL, 38.7µg/mL and 100.5µg/mL for the 3 favipiravir doses.…”

Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort

“…Interestingly, we here considered, for the sake of simplicity, treatments blocking viral production, but largely similar results could be obtained with drugs that would block infection, as is the case for monoclonal antibodies. This level of 90% is not out of reach, and roughly corresponds to drug concentrations being 10 times higher than their EC 50 (concentration for which 50% of maximum effect is obtained), which are standard for antiviral drugs in other infections [e.g., HIV, hepatitis B virus , hepatitis C virus, Ebola ( 41 )]. Given the fact that peak viral load occurs early, as discussed above, it is likely that aggressive strategies that could identify patients earlier than in our study (where admission occurred, on average, 7 d after symptom onset) could have even better results.…”

A review on pharmacokinetics, pharmacodynamics and clinical aspects of remdesivir and favipiravir for the treatment of coronavirus disease

“…It acts by direct restraint of viral replication and records through misincorporation in nascent vRNA (viral ribonucleic corrosive), or by binding to preserved polymerase domains, preventing incorporation of nucleotides for vRNA replication and transcription. 6,41 According to Madelain V et al 42 In an open-label non-randomized control study led by Q Cai et al, favipiravir (FPV) 1600 mg twice day by day as a loading dose and 600mg twice every day in addition to interferon (IFN). In another group lopinavir 400 mg/ritonavir 100mg (RTV) twice every day in addition to IFN.…”