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

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cam.issuedOnline2021-11-13
datacite.isderivedfrom.doi10.1101/2021.09.10.21263376
dc.contributor.authorWalker, Lauren E
dc.contributor.authorFitzGerald, Richard
dc.contributor.authorSaunders, Geoffrey
dc.contributor.authorLyon, Rebecca
dc.contributor.authorFisher, Michael
dc.contributor.authorMartin, Karen
dc.contributor.authorEberhart, Izabela
dc.contributor.authorWoods, Christie
dc.contributor.authorEwings, Sean
dc.contributor.authorHale, Colin
dc.contributor.authorRajoli, Rajith KR
dc.contributor.authorElse, Laura
dc.contributor.authorDilly-Penchala, Sujan
dc.contributor.authorAmara, Alieu
dc.contributor.authorLalloo, David G
dc.contributor.authorJacobs, Michael
dc.contributor.authorPertinez, Henry
dc.contributor.authorHatchard, Parys
dc.contributor.authorWaugh, Robert
dc.contributor.authorLawrence, Megan
dc.contributor.authorJohnson, Lucy
dc.contributor.authorFines, Keira
dc.contributor.authorReynolds, Helen
dc.contributor.authorRowland, Timothy
dc.contributor.authorCrook, Rebecca
dc.contributor.authorOkenyi, Emmanuel
dc.contributor.authorByrne, Kelly
dc.contributor.authorMozgunov, Pavel
dc.contributor.authorJaki, Thomas
dc.contributor.authorKhoo, Saye
dc.contributor.authorOwen, Andrew
dc.contributor.authorGriffiths, Gareth
dc.contributor.authorFletcher, Thomas E
dc.contributor.authorAGILE platform
dc.contributor.orcidFisher, Michael [0000-0003-2304-6434]
dc.contributor.orcidMartin, Karen [0000-0002-6362-0501]
dc.contributor.orcidReynolds, Helen [0000-0001-7443-4520]
dc.contributor.orcidByrne, Kelly [0000-0001-8895-5618]
dc.contributor.orcidKhoo, Saye [0000-0002-2769-0967]
dc.contributor.orcidOwen, Andrew [0000-0002-9819-7651]
dc.date.accessioned2022-01-06T11:52:06Z
dc.date.available2022-01-06T11:52:06Z
dc.date.issued2022-03
dc.date.updated2022-01-06T11:52:06Z
dc.descriptionFunder: Unitaid
dc.description.abstractRepurposing 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.
dc.identifier.doi10.17863/CAM.79624
dc.identifier.eissn1532-6535
dc.identifier.issn0009-9236
dc.identifier.otherPMC8653087
dc.identifier.other34699618
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332178
dc.languageeng
dc.language.isoeng
dc.publisherWiley
dc.publisher.urlhttp://dx.doi.org/10.1002/cpt.2463
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1532-6535
dc.sourcenlmid: 0372741
dc.subjectAdult
dc.subjectAntiviral Agents
dc.subjectDrug Repositioning
dc.subjectFemale
dc.subjectHealthy Volunteers
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectNitro Compounds
dc.subjectThiazoles
dc.subjectYoung Adult
dc.subjectCOVID-19 Drug Treatment
dc.titleAn Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.
dc.typeArticle
dcterms.dateAccepted2021-10-16
prism.publicationNameClin Pharmacol Ther
pubs.funder-project-idUK Research and Innovation (MR/V028391/1)
pubs.funder-project-idWellcome Trust (221590/Z/20/Z)
pubs.funder-project-idMedical Research Council (MC_UU_00002/14)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1002/cpt.2463

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