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Clinical Trial
. 2022 Mar;111(3):585-594.
doi: 10.1002/cpt.2463. Epub 2021 Nov 13.

An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2

Lauren E Walker  1   2 , Richard FitzGerald  2 , Geoffrey Saunders  3 , Rebecca Lyon  2 , Michael Fisher  1   2 , Karen Martin  3 , Izabela Eberhart  3 , Christie Woods  2 , Sean Ewings  3 , Colin Hale  2 , Rajith K R Rajoli  1 , Laura Else  1 , Sujan Dilly-Penchala  1 , Alieu Amara  1 , David G Lalloo  4 , Michael Jacobs  4 , Henry Pertinez  1 , Parys Hatchard  3 , Robert Waugh  3 , Megan Lawrence  3 , Lucy Johnson  3 , Keira Fines  3 , Helen Reynolds  1 , Timothy Rowland  2 , Rebecca Crook  2 , Emmanuel Okenyi  2 , Kelly Byrne  4 , Pavel Mozgunov  5 , Thomas Jaki  5 , Saye Khoo  1 , Andrew Owen  1 , Gareth Griffiths  3 , Thomas E Fletcher  2   4 ; AGILE platform
Affiliations
Clinical Trial

An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2

Lauren E Walker et al. Clin Pharmacol Ther. 2022 Mar.

Abstract

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.

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Conflict of interest statement

A.O. is Director 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. Ridgeback and GlaxoSmithKline have provided funding to the AGILE phase I/II platform to evaluate SARS‐CoV‐2 candidates independently of the current trial. G.G. has received funding from Janssen‐Cilag, Astra Zeneca, Novartis, Astex, Roche, Heartflow, Celldex, BMS, BionTech, Cancer Research UK, NIHR, British Lung Foundation, Unitaid, and GSK for unrelated academic clinical trials and program funding. S.K. has received funding from Merck, ViiV, Janssen, and Gilead for unrelated academic trials. All other authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
CONSORT diagram. BMI, body mass index; PI, principal investigator. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Simultaneous one‐compartment, first order absorption parent‐metabolite PK model fitting to naïve pooled tizoxanide (parent) and tizoxanide‐glucuronide (metabolite) plasma concentration data. The red line represents the in vitro derived EC90 against SARS‐CoV‐2 (1.43 mg/L). Conc, concentration; EC90, effective concentration 90%; GLU, glucuronide; PK, pharmacokinetic; SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus 2; TIZ, tizoxanide. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Comparison of PBPK simulated and observed tizoxanide plasma concentrations. (a) comparison of median (SD) simulated concentrations (blue) against the naïve pool of plasma concentration in healthy individuals. (b) Comparison of observed and simulated median (95% CI) tizoxanide plasma concentrations following the first dose. (c) Comparison of observed and simulated median (95% CI) tizoxanide plasma concentrations on day 5. The red line represents the in vitro derived EC90 against SARS‐CoV‐2 (1.43 mg/L; 5.4 µm). CI, confidence interval; EC90, effective concentration 90%; PBPK, physiologically‐based pharmacokinetic; SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus 2; TIZ, tizoxanide. [Colour figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

References

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