{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T03:30:46Z","timestamp":1782790246718,"version":"3.54.5"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,11,13]],"date-time":"2021-11-13T00:00:00Z","timestamp":1636761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:p>\n                    Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID\u201019), but repurposed antivirals have not been successful to date because of redundancy of the target\n                    <jats:italic>in vivo<\/jats:italic>\n                    or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically\u2010based 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\u2010dose nitazoxanide. Participants received 1,500\u00a0mg nitazoxanide orally twice\u2010daily with food for 7\u00a0days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (C\n                    <jats:sub>min<\/jats:sub>\n                    ) 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\u2010limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median C\n                    <jats:sub>min<\/jats:sub>\n                    was above the\n                    <jats:italic>in vitro<\/jats:italic>\n                    target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500\u00a0mg b.i.d. with food was safe with acceptable tolerability a phase Ib\/IIa study is now being initiated in patients with COVID\u201019.\n                  <\/jats:p>","DOI":"10.1002\/cpt.2463","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T16:04:33Z","timestamp":1635264273000},"page":"585-594","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["An Open Label, Adaptive, Phase 1 Trial of High\u2010Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS\u2010CoV\u20102"],"prefix":"10.1111","volume":"111","author":[{"given":"Lauren E.","family":"Walker","sequence":"first","affiliation":[{"name":"University of Liverpool Liverpool UK"},{"name":"Liverpool University Hospitals NHS Foundation Trust Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"FitzGerald","sequence":"additional","affiliation":[{"name":"Liverpool University Hospitals NHS Foundation Trust Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Saunders","sequence":"additional","affiliation":[{"name":"Southampton Clinical Trials Unit University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Lyon","sequence":"additional","affiliation":[{"name":"Liverpool University Hospitals NHS Foundation Trust Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2304-6434","authenticated-orcid":false,"given":"Michael","family":"Fisher","sequence":"additional","affiliation":[{"name":"University of Liverpool Liverpool UK"},{"name":"Liverpool University Hospitals NHS Foundation Trust Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6362-0501","authenticated-orcid":false,"given":"Karen","family":"Martin","sequence":"additional","affiliation":[{"name":"Southampton Clinical Trials Unit University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Eberhart","sequence":"additional","affiliation":[{"name":"Southampton Clinical Trials Unit University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christie","family":"Woods","sequence":"additional","affiliation":[{"name":"Liverpool University Hospitals NHS Foundation Trust Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Ewings","sequence":"additional","affiliation":[{"name":"Southampton Clinical Trials Unit University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Hale","sequence":"additional","affiliation":[{"name":"Liverpool University Hospitals NHS Foundation Trust Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajith K. 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