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. 2021 Apr;87(4):2078-2088.
doi: 10.1111/bcp.14619. Epub 2020 Dec 1.

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

Rajith K R Rajoli  1 , Henry Pertinez  1 , Usman Arshad  1 , Helen Box  1 , Lee Tatham  1 , Paul Curley  1 , Megan Neary  1 , Joanne Sharp  1 , Neill J Liptrott  1 , Anthony Valentijn  1 , Christopher David  1 , Steven P Rannard  2 , Ghaith Aljayyoussi  3 , Shaun H Pennington  3 , Andrew Hill  1 , Marta Boffito  4   5 , Steve A Ward  3 , Saye H Khoo  1 , Patrick G Bray  6 , Paul M O'Neill  2 , W David Hong  2 , Giancarlo A Biagini  3 , Andrew Owen  1
Affiliations

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

Rajith K R Rajoli et al. Br J Clin Pharmacol. 2021 Apr.

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 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 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 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 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.

Keywords: COVID-19; SARS-CoV-2; coronavirus; lung; pharmacokinetics.

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Conflict of interest statement

A.O. and S.P.R. are Directors of Tandem Nano Ltd. A.O. has received research funding from ViiV, Merck, Janssen and consultancy from Gilead, ViiV and Merck not related to the current paper. P.O.N. is currently engaged in a collaboration with Romark LLC but this interaction did not influence the prioritisation or conclusions in the current manuscript. No other conflicts are declared by the authors.

Figures

FIGURE 1
FIGURE 1
Simulated plasma A, and lung B, concentrations for nitazoxanide 600 mg BID for 5 days with food relative to the average reported tizoxanide EC90 value for influenza strains (Supporting Information Table S1) similar to those in a previous phase 2b/3 trial in uncomplicated influenza 30
FIGURE 2
FIGURE 2
A, Predicted tizoxanide C trough (BID 12 hours, TID 8 hours, QID 6 hours) for various dosing regimens of nitazoxanide in the fasted state at the end of the first dose. Data are presented as means and error bars represent standard deviation. The percentages adjacent to the bar chart indicate the percentages of simulated population over EC90 of nitazoxanide for SARS‐CoV‐2. B, Predicted tizoxanide C trough (BID 12 hours, TID 8 hours, QID 6 hours) for various dosing regimens of nitazoxanide in the fed state at the end of the first dose. Data are presented as means and error bars represent standard deviation. The percentages adjacent to the bar chart indicate the percentages of simulated population over EC90 of nitazoxanide for SARS‐CoV‐2
FIGURE 3
FIGURE 3
Predicted plasma and lung concentrations for optimal doses during the fed state at different regimens reaching steady state: A, 1400 mg BID, B, 900 mg TID and C, 700 mg QID. TIZ, tizoxanide; SD, standard deviation. The solid red line indicates clinical C max of a 1 g single dose at the fed state, 35 the solid green line represents clinical C max of a 500 mg single dose 62 at the fed state and the dotted red line represents the EC90 of nitazoxanide for SARS‐CoV‐2 18
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