Walker, Lauren E 
ORCID: 0000-0002-3827-4387, FitzGerald, Richard, Saunders, Geoffrey, Lyon, Rebecca, Fisher, Michael, Martin, Karen, Eberhart, Izabela, Woods, Christie, Ewings, Sean, Hale, Colin et al (show 23 more authors)
(2022)
An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.
CLINICAL PHARMACOLOGY & THERAPEUTICS, 111 (3).
pp. 585-594.
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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 (C<sub>min</sub> ) 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 C<sub>min</sub> 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | AGILE platform, Humans, Nitro Compounds, Thiazoles, Antiviral Agents, Adult, Middle Aged, Female, Male, Young Adult, Drug Repositioning, Healthy Volunteers, COVID-19 Drug Treatment |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 01 Nov 2021 08:23 |
| Last Modified: | 07 Feb 2023 15:23 |
| DOI: | 10.1002/cpt.2463 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3142042 |
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