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?:abstract
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To face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach. A multi-stage model-based approach was developed to characterize % of recovery and viral load in CCoV-infected dogs, to estimate the PK of indomethacin in dog and human using published data after administration of immediate (IR) and sustained-release (SR) formulations, and to estimate the expected antiviral activity as a function of different assumptions on the effective exposure in human. Different dosage regimens were evaluated for IR formulation (25 mg and 50 mg three-times-a-day, and 25 mg four-times-a-day), and SR formulation (75 mg once and twice-a-day). The best performing dosing regimens were: 50 mg three-times-a-day for the IR formulation, and 75 mg twice-a-day for the SR formulation. The treatment with the SR formulation at the dose of 75 mg twice-a-day is expected to achieve a complete response in three days for the treatment in patients infected by the SARS-CoV-2 coronavirus. These results suggest that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 whose potential therapeutic effect need to be further assessed in a prospective clinical trial. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10928-020-09690-4) contains supplementary material, which is available to authorized users.
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?:doi
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10.1007/s10928-020-09690-4
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J_Pharmacokinet_Pharmacodyn
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document_parses/pdf_json/72c595200f501da29e05e6ee2bf129b993144e34.json; document_parses/pdf_json/7aa3762bb8c14604892d75d84d743d2b8afb45c8.json
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document_parses/pmc_json/PMC7237801.xml.json
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?:title
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Model based approach for estimating the dosage regimen of indomethacin a potential antiviral treatment of patients infected with SARS CoV-2
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