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Dose Prediction for Repurposing Nitazoxanide in SARS-CoV-2 Treatment or Chemoprophylaxis
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  • Rajith Rajoli,
  • Henry Pertinez,
  • Usman Arshad,
  • Helen Box,
  • Lee Tatham,
  • Paul Curley,
  • Megan Neary,
  • Joanne Sharp,
  • Neill Liptrott ,
  • Anthony Valentijn,
  • Christopher David,
  • Steven Rannard,
  • Ghaith Aljayyoussi,
  • Shaun Pennington,
  • Andrew Hill,
  • Marta Boffito,
  • Steve Ward,
  • Saye Khoo,
  • Patrick Bray,
  • Paul O'Neill,
  • W. Hong,
  • Giancarlo Biagini,
  • Andrew Owen
Rajith Rajoli
University of Liverpool
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Henry Pertinez
University of Liverpool
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Usman Arshad
University of Liverpool
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Helen Box
University of Liverpool
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Lee Tatham
University of Liverpool
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Paul Curley
University of Liverpool
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Megan Neary
University of Liverpool
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Joanne Sharp
University of Liverpool
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Neill Liptrott
University of Liverpool
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Anthony Valentijn
University of Liverpool
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Christopher David
University of Liverpool
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Steven Rannard
University of Liverpool
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Ghaith Aljayyoussi
Liverpool School of Tropical Medicine
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Shaun Pennington
Liverpool School of Tropical Medicine
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Andrew Hill
University of Liverpool
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Marta Boffito
Chelsea and Westminster Hospital NHS Foundation Trust
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Steve Ward
Liverpool School of Tropical Medicine
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Saye Khoo
University of Liverpool
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Patrick Bray
Pat Bray Electrical
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Paul O'Neill
University of Liverpool
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W. Hong
University of Liverpool
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Giancarlo Biagini
Liverpool School of Tropical Medicine
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Andrew Owen
University of Liverpool
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Abstract

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 nitazoxanide SARS-CoV-2 EC90. Methods: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500–4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the nitazoxanide EC90 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, 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 12h 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.

Peer review status:UNDER REVIEW

12 May 2020Submitted to British Journal of Clinical Pharmacology
13 May 2020Submission Checks Completed
13 May 2020Assigned to Editor
18 May 2020Reviewer(s) Assigned
26 Jul 2020Review(s) Completed, Editorial Evaluation Pending
07 Aug 2020Editorial Decision: Revise Major
10 Sep 20201st Revision Received
11 Sep 2020Assigned to Editor
11 Sep 2020Submission Checks Completed
11 Sep 2020Review(s) Completed, Editorial Evaluation Pending