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

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.

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“…In this absence of effective anti-COVID-19 therapy, some researchers have suggested the repurposing of the known potent antiinfluenza drug favipiravir (chemically, it is a purine nucleoside analog; approved for medical use in Japan since 2014; Fig. 2 ) to counteract the novel COVID-19 (Shiraki and Daikoku 2020 ; Dong et al 2020 ; Łagocka et al 2021 ; Driouich et al 2021 ). Previous studies identified viral RNA-dependent RNA polymerase (RdRp) as a potential drug target in COVID-19 treatment due to its crucial role in SARS-CoV-2 replication and transcription (i.e., in the virus life cycle) (Zhang and Tang 2021 ).…”

Probenecid Inhibits SARS-CoV-2 Replication In Vivo and In Vitro

“…Six dosing groups were tested: a) two prophylaxis groups treated with doses of 2 mg/kg or 200 mg/kg, b) two post-treatment groups treated with doses of 2 mg/kg or 200 mg/kg, and two control groups that were infected or not infected. Disease in hamsters following SARS-CoV-2 infection was transient peaking around day 3-4 post-infection with no clinical signs 17 . Consistent with this observation, no clinical symptoms or weight loss was evident in any group throughout the study (Supplementary Figure 1).…”

“…Having shown in vitro efficacy and determined the IC50 values, we next determined the efficacy of probenecid in the hamster model regarded as a preclinical model of SARS-CoV-2 disease with hamsters having self-limiting pneumonia 17,18 . We examined hamsters infected with SARS-CoV-2 and treated them with probenecid for either 24h before infection (prophylaxis) or 48h post-infection (post-treatment).…”

Coronavirus Disease 2019 and Kidney Transplantation in Saudi Arabia: Outcomes and Future Opportunities

“…Recent reports from the RECOVERY and REMAP-CAP trials showed that treatment with tocilizumab led to lower mortality across patients with different disease severities [ 18 , 19 ]. Two studies using a hamster model of SARS-CoV-2 infection have shown a modest antiviral effect of favipiravir [ 20 , 21 ]. In a retrospective study from 2 hospitals in SA, use of favipiravir was associated with accelerated discharge rate and less progression to mechanical ventilation, but no overall mortality benefits [ 22 ].…”