Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity
Kaptein et al.,
Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas..,
bioRxiv, doi:10.1101/2020.06.19.159053
Animal study with Syrian hamsters, showing treatment of SARS-CoV-2-infected hamsters with favipiravir or HCQ (with and without AZ). Treatment with HCQ alone resulted in a very modest reduction of 0.3 log10 viral RNA copies/mg lung, and no reduction in viral RNA load in the ileum or stool.
Therapeutic levels of HCQ may not have been reached. Cytosolic concentrations in the lung were far below the EC90 target.
A number of issues have reportedly been raised, including the following, for which the authors did not respond:
- HCQ was administered with DMSO and Cremophor - why were non-neutral carriers chosen? DMSO has anti-inflammatory properties and Cremophor has a range of side effects
[sciencedirect.com]: "use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy". Why weren't the same amounts of solvent applied to the non-treated animals? Shouldn't favipiravir have been dissolved in the same way to avoid bias?
- Why is the method of administration different for both products (oral gavage/intraperitoneal injection)?
- One of the HCQ protocols used in France (IHU Marseille) prescribes 600mg of HCQ per day to patients. For a body weight of 60kg, this corresponds to a dose of 10mg/kg. How is a dose of 50 mg/kg in this study justified, i.e. 5 times more, with possible systemic effects on the animals and possible influence on the results?
- Why were the animals killed after 4/5 days and did the treatment not continue? Unfortunately, this does not allow us to know the real course of the disease or the mortality of the animals beyond day 4. Is it because the animals spontaneously improve without treatment as Professor Neyts seems to say in his webinar for the GVN? And if this is indeed the case, isn't the use of these hamsters exactly an objection as a model for COVID-19 research?
Kaptein et al., 19 Jun 2020, peer-reviewed, 35 authors.
Abstract: Favipiravir at high doses has potent antiviral activity
in SARS-CoV-2−infected hamsters, whereas
hydroxychloroquine lacks activity
a
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research,
Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; bBiomedical MRI and Molecular Small Animal Imaging Centre, Department of Imaging and
Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; cDrug Delivery & Disposition, Department of Pharmaceutical and Pharmacological
Sciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; dUnité des Virus Emergents, Aix Marseille University, Institut de Recherche pour le
Développement (IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207, 13005 Marseille, France; eUCL Great Ormond Street
Institute of Child Health, University College London, WC1N 1EH London, United Kingdom; f Molecular Small Animal Imaging Centre, Department of
Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; gDepartment of Laboratory Medicine, Ghent University Hospital, 9000
Ghent, Belgium; hNuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven,
Belgium; iAssistance Publique–Hôpitaux de Marseille, Aix-Marseille University, Unité des Virus Emergents, Institut de Recherche pour le Développement
(IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207, Laboratoire de Pharmacocinétique et Toxicologie, 13005 Marseille,
France; jTranslational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; kPharmacy
Department, University Hospitals Leuven, 3000 Leuven, Belgium; lDepartment of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit
Leuven–University of Leuven, 3000 Leuven, Belgium; and mGlobal Virus Network, Baltimore, MD 21201
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved September 3, 2020 (received for review July 9, 2020)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
rapidly spread around the globe after its emergence in Wuhan in
December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which
more than half a million succumbed to the viral disease, COVID-19.
The urgent need for an effective treatment together with a lack of
small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy.
We established an infection model in Syrian hamsters to evaluate
the efficacy of small molecules on both infection and transmission.
Treatment of SARS-CoV-2−infected hamsters with a low dose of
favipiravir or hydroxychloroquine with(out) azithromycin resulted
in, respectively, a mild or no reduction in virus levels. However, high
doses of favipiravir significantly reduced infectious virus titers in the
lungs and markedly improved lung histopathology. Moreover, a
high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total
lung exposure to the drug did not cause the failure. Our data on
hydroxychloroquine (together with previous reports in macaques
and ferrets) thus provide no scientific basis for the..
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