Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.

Tytuł:: Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.
Autorzy:: Rajoli RKR; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Pertinez H; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Arshad U; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Box H; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Tatham L; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Curley P; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Neary M; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Sharp J; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Liptrott NJ; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Valentijn A; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
David C; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Rannard SP; Department of Chemistry, University of Liverpool, Liverpool, UK.
Aljayyoussi G; Centre for Drugs and Diagnostics, and Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
Pennington SH; Centre for Drugs and Diagnostics, and Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
Hill A; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Boffito M; Chelsea and Westminster NHS Foundation Trust and St Stephen's AIDS Trust 4th Floor, Chelsea and Westminster Hospital, London, UK.; Jefferiss Research Trust Laboratories, Department of Medicine, Imperial College, London, UK.
Ward SA; Centre for Drugs and Diagnostics, and Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
Khoo SH; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Bray PG; Pat Bray Electrical, Orrell, Wigan, UK.
O'Neill PM; Department of Chemistry, University of Liverpool, Liverpool, UK.
Hong WD; Department of Chemistry, University of Liverpool, Liverpool, UK.
Biagini GA; Centre for Drugs and Diagnostics, and Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
Owen A; Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.
Źródło:: British journal of clinical pharmacology [Br J Clin Pharmacol] 2021 Apr; Vol. 87 (4), pp. 2078-2088. Date of Electronic Publication: 2020 Dec 01.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Validation Study
Język:: English
Imprint Name(s):: Publication: Oxford : Wiley-Blackwell
Original Publication: London, Macmillan Journals Ltd.
MeSH Terms:: Drug Repositioning*
Models, Biological*
COVID-19 Drug Treatment*
Antiviral Agents/*administration & dosage
COVID-19/*prevention & control
Nitro Compounds/*administration & dosage
Thiazoles/*administration & dosage
Adult ; Antiviral Agents/blood ; Antiviral Agents/pharmacokinetics ; COVID-19/blood ; Computer Simulation ; Drug Dosage Calculations ; Female ; Humans ; Lung/metabolism ; Male ; Middle Aged ; Nitro Compounds/blood ; Nitro Compounds/pharmacokinetics ; Reproducibility of Results ; Thiazoles/blood ; Thiazoles/pharmacokinetics ; Tissue Distribution ; Young Adult
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Grant Information:: R01 AI134091 United States AI NIAID NIH HHS; MR/S00467X/1 United Kingdom MRC_ Medical Research Council; R24 AI118397 United States AI NIAID NIH HHS; R24AI118397 United States GF NIH HHS; MR/V028391/1 United Kingdom MRC_ Medical Research Council; R01AI134091 United States GF NIH HHS; MC_PC_17167 United Kingdom MRC_ Medical Research Council
Contributed Indexing:: Keywords: COVID-19; SARS-CoV-2; coronavirus; lung; pharmacokinetics
Substance Nomenclature:: 0 (Antiviral Agents)
0 (Nitro Compounds)
0 (Thiazoles)
SOA12P041N (nitazoxanide)
Entry Date(s):: Date Created: 20201021 Date Completed: 20210331 Latest Revision: 20240216
Update Code:: 20240216
PubMed Central ID:: PMC8056737
DOI:: 10.1111/bcp.14619
PMID:: 33085781
: Czasopismo naukowe

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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC 90 .
Methods: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC 90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.
Results: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated.
Conclusion: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.
(© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Update of: medRxiv. 2020 May 06;:. (PMID: 32511548)

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