Abstract
Despite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2. Here we use a Syrian hamster model to assess the antiviral efficacy of favipiravir, understand its mechanism of action and determine its pharmacokinetics. When treatment is initiated before or simultaneously to infection, favipiravir has a strong dose effect, leading to reduction of infectious titers in lungs and clinical alleviation of the disease. Antiviral effect of favipiravir correlates with incorporation of a large number of mutations into viral genomes and decrease of viral infectivity. Antiviral efficacy is achieved with plasma drug exposure comparable with those previously found during human clinical trials. Notably, the highest dose of favipiravir tested is associated with signs of toxicity in animals. Thereby, pharmacokinetic and tolerance studies are required to determine whether similar effects can be safely achieved in humans.
Highlights
Despite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2
Favipiravir is a prodrug that is metabolized intracellularly into its active ribonucleoside 5′-triphosphate form that acts as a nucleotide analog to selectively inhibit RNA-dependent RNA polymerase and induce lethal mutagenesis[16,17]
We evaluate the efficacy of favipiravir in vitro and using a Syrian hamster model (Mesocricetus auratus)
Summary
Despite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2. When treatment is initiated before or simultaneously to infection, favipiravir has a strong dose effect, leading to reduction of infectious titers in lungs and clinical alleviation of the disease. The development of effective antiviral drugs for the treatment of COVID-19, should, as much as possible, rely on robust pre-clinical in vivo data, on efficacy generated in vitro. Several studies reported in vitro inhibitory activity of favipiravir against SARS-CoV-2 with 50% effective concentrations (EC50) ranging from 62 to > 500 μM (10 to > 78 μg/mL)[18,19,20] Based on these results, more than 20 clinical trials on the management of COVID-19 by favipiravir are ongoing (https://clinicaltrials.gov/). Our results show that preventive or preemptive administration of high doses favipiravir induce significant reduction of infectious titers and histopathological damages in lungs and clinical alleviation of the disease. Analysis of genetic diversity of viral populations in lungs confirms the mutagenic effect of favipiravir
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