Dose Prediction for Repurposing Nitazoxanide in SARS‐CoV‐2 Treatment or Chemoprophylaxis

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

doi:10.1111/bcp.14619

Dose Prediction for Repurposing Nitazoxanide in SARS‐CoV‐2 Treatment or Chemoprophylaxis

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

Tropical Disease Biology

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

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 500–4000 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, 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. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial (www.agiletrial.net).

Original language	English
Pages (from-to)	2078-2088
Number of pages	11
Journal	British Journal of Clinical Pharmacology
Volume	87
Issue number	4
Early online date	21 Oct 2020
DOIs	https://doi.org/10.1111/bcp.14619
Publication status	Published - 1 Apr 2021

Keywords

coronavirus
COVID-19
lung
pharmacokinetics
SARS-CoV-2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Rajoli, R. K. R., Pertinez, H., Arshad, U., Box, H., Tatham, L., Curley, P., Neary, M., Sharp, J., Liptrott, N. J., Valentijn, A., David, C., Rannard, S. P., Aljayyoussi, G., Pennington, S., Hill, A., Boffito, M., Ward, S., Khoo, S. H., Bray, P. G., ... Owen, A. (2021). Dose Prediction for Repurposing Nitazoxanide in SARS‐CoV‐2 Treatment or Chemoprophylaxis. British Journal of Clinical Pharmacology, 87(4), 2078-2088. https://doi.org/10.1111/bcp.14619

@article{6110793c2d3e4df38bca3dac368c6452,

title = "Dose Prediction for Repurposing Nitazoxanide in SARS‐CoV‐2 Treatment or Chemoprophylaxis",

abstract = "BackgroundSevere 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.MethodsA 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 EC90 in >90\% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.ResultsThe 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.ConclusionThe 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 (www.agiletrial.net).",

keywords = "coronavirus, COVID-19, lung, pharmacokinetics, SARS-CoV-2",

author = "Rajoli, \{Rajith K.R.\} and Henry Pertinez and Usman Arshad and Helen Box and Lee Tatham and Paul Curley and Megan Neary and Joanne Sharp and Liptrott, \{Neill J.\} and Anthony Valentijn and Christopher David and Rannard, \{Steven P.\} and Ghaith Aljayyoussi and Shaun Pennington and Andrew Hill and Marta Boffito and Steve Ward and Khoo, \{Saye H.\} and Bray, \{Patrick G.\} and O'Neill, \{Paul M.\} and Hong, \{W. David\} and Giancarlo Biagini and Andrew Owen",

year = "2021",

month = apr,

day = "1",

doi = "10.1111/bcp.14619",

language = "English",

volume = "87",

pages = "2078--2088",

journal = "British Journal of Clinical Pharmacology",

issn = "0306-5251",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "4",

}

Rajoli, RKR, Pertinez, H, Arshad, U, Box, H, Tatham, L, Curley, P, Neary, M, Sharp, J, Liptrott, NJ, Valentijn, A, David, C, Rannard, SP, Aljayyoussi, G, Pennington, S, Hill, A, Boffito, M, Ward, S, Khoo, SH, Bray, PG, O'Neill, PM, Hong, WD, Biagini, G & Owen, A 2021, 'Dose Prediction for Repurposing Nitazoxanide in SARS‐CoV‐2 Treatment or Chemoprophylaxis', British Journal of Clinical Pharmacology, vol. 87, no. 4, pp. 2078-2088. https://doi.org/10.1111/bcp.14619

TY - JOUR

T1 - Dose Prediction for Repurposing Nitazoxanide in SARS‐CoV‐2 Treatment or Chemoprophylaxis

AU - Rajoli, Rajith K.R.

AU - Pertinez, Henry

AU - Arshad, Usman

AU - Box, Helen

AU - Tatham, Lee

AU - Curley, Paul

AU - Neary, Megan

AU - Sharp, Joanne

AU - Liptrott, Neill J.

AU - Valentijn, Anthony

AU - David, Christopher

AU - Rannard, Steven P.

AU - Aljayyoussi, Ghaith

AU - Pennington, Shaun

AU - Hill, Andrew

AU - Boffito, Marta

AU - Ward, Steve

AU - Khoo, Saye H.

AU - Bray, Patrick G.

AU - O'Neill, Paul M.

AU - Hong, W. David

AU - Biagini, Giancarlo

AU - Owen, Andrew

PY - 2021/4/1

Y1 - 2021/4/1

N2 - BackgroundSevere 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.MethodsA 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 EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.ResultsThe 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.ConclusionThe 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 (www.agiletrial.net).

AB - BackgroundSevere 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.MethodsA 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 EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.ResultsThe 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.ConclusionThe 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 (www.agiletrial.net).

KW - coronavirus

KW - COVID-19

KW - lung

KW - pharmacokinetics

KW - SARS-CoV-2

U2 - 10.1111/bcp.14619

DO - 10.1111/bcp.14619

M3 - Article

SN - 0306-5251

VL - 87

SP - 2078

EP - 2088

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

IS - 4

ER -

Dose Prediction for Repurposing Nitazoxanide in SARS‐CoV‐2 Treatment or Chemoprophylaxis

Abstract

Keywords

UN SDGs

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