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

Walker, Lauren, Fitzgerald, Richard, Saunders, Geoffrey, Lyon, Rebecca, Fisher, Michael, Martin, Karen, Eberhardt, Izabela, Woods, Christie, Ewings, Sean, Hale, Colin, Rajoli, Rajith, Else, Laura, Dilly-Penchala, Sujan, Amara, Alieu, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Jacobs, Michael, Pertinez, Henry, Hatchard, Parys, Waugh, Robert, Lawrence, Megan, Johnson, Lucy, Fines, Keira, Reynolds, Helen, Rowland, Timothy, Crook, Rebecca, Okenyi, Emmanuel, Byrne, Kelly, Mozgunov, Pavel, Jaki, Thomas, Khoo, Saye, Owen, Andrew, Griffiths, Gareth and Fletcher, Tom (2021) 'An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2'. Clinical Pharmacology and Therapeutics, Vol 111, Issue 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 1500 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.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 268.5 Antiviral agents (General) QW Microbiology and Immunology > Viruses > QW 160 Viruses (General). Virology WA Public Health > WA 105 Epidemiology WC Communicable Diseases > Virus Diseases > Viral Respiratory Tract Infections. Respirovirus Infections > WC 505 Viral respiratory tract infections
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1002/cpt.2463
Depositing User:	Christine Bradbury
Date Deposited:	30 Nov 2021 14:45
Last Modified:	06 Apr 2022 14:08
URI:	https://archive.lstmed.ac.uk/id/eprint/19536

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