An Open Label, Adaptive, Phase 1 Trial of High‐Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS‐CoV‐2
Dr Lauren E Walker, Richard Fitzgerald, Geoffrey Saunders, Rebecca Lyon, Michael Fisher, Karen Martin, Izabela Eberhart, Christie Woods, Sean Ewings, Colin Hale, Rajith K R Rajoli, Laura Else, Sujan Dilly‐penchala, Alieu Amara, David G Lalloo, Michael Jacobs, Henry Pertinez, Parys Hatchard, Robert Waugh, Megan Lawrence, Lucy Johnson, Keira Fines, Helen Reynolds, Timothy Rowland, Rebecca Crook, Emmanuel Okenyi, Kelly Byrne, Pavel Mozgunov, Thomas Jaki, Saye Khoo, Andrew Owen, Gareth Griffiths, Thomas E Fletcher
Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.2463
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.
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'abstract': '<jats:p>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 <jats:italic>in vivo</jats:italic> 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\xa0mg nitazoxanide orally twice‐daily with food for 7\xa0days. '
'Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive '
'pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration '
'(C<jats:sub>min</jats: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<jats:sub>min</jats:sub> was above the <jats:italic>in vitro</jats:italic> '
'target concentration on the first dose and maintained throughout. Nitazoxanide administered '
'at 1,500\xa0mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is '
'now being initiated in patients with COVID‐19.</jats:p>',
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'title': 'An Open Label, Adaptive, Phase 1 Trial of High‐Dose Oral Nitazoxanide in Healthy Volunteers: An '
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