tetano
Editor, Senior Moderator
Clin Pharmacol Ther
. 2021 Oct 26.
doi: 10.1002/cpt.2463. Online ahead of print.
An open label, adaptive, phase 1 trial of high-dose oral nitazoxanide in healthy volunteers: an antiviral candidate for SARS-CoV-2
Lauren E Walker[SUP] 1 2 [/SUP], Richard FitzGerald[SUP] 2 [/SUP], Geoffrey Saunders[SUP] 3 [/SUP], Rebecca Lyon[SUP] 2 [/SUP], Michael Fisher[SUP] 1 2 [/SUP], Karen Martin[SUP] 3 [/SUP], Izabela Eberhart[SUP] 3 [/SUP], Christie Woods[SUP] 2 [/SUP], Sean Ewings[SUP] 3 [/SUP], Colin Hale[SUP] 2 [/SUP], Rajith Kr Rajoli[SUP] 1 [/SUP], Laura Else[SUP] 1 [/SUP], Sujan Dilly-Penchala[SUP] 1 [/SUP], Alieu Amara[SUP] 1 [/SUP], David G Lalloo[SUP] 4 [/SUP], Michael Jacobs[SUP] 4 [/SUP], Henry Pertinez[SUP] 1 [/SUP], Parys Hatchard[SUP] 3 [/SUP], Robert Waugh[SUP] 3 [/SUP], Megan Lawrence[SUP] 3 [/SUP], Lucy Johnson[SUP] 3 [/SUP], Keira Fines[SUP] 3 [/SUP], Helen Reynolds[SUP] 1 [/SUP], Timothy Rowland[SUP] 2 [/SUP], Rebecca Crook[SUP] 2 [/SUP], Emmanuel Okenyi[SUP] 2 [/SUP], Kelly Byrne[SUP] 4 [/SUP], Pavel Mozgunov[SUP] 5 [/SUP], Thomas Jaki[SUP] 5 [/SUP], Saye Khoo[SUP] 1 [/SUP], Andrew Owen[SUP] 1 [/SUP], Gareth Griffiths[SUP] 3 [/SUP], Thomas E Fletcher[SUP] 2 4 [/SUP], AGILE platform
Affiliations
Abstract
Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe 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 an FDA approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modelling 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 1 trial in healthy adult participants was undertaken with high dose nitazoxanide. Participants received 1500mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose and schedule. Intensive pharmacokinetic sampling was undertaken day 1 and 5 with Cmin sampling on day 3 and 7. Fourteen healthy participants were enrolled between 18[SUP]th[/SUP] February and 11[SUP]th[/SUP] May 2021. All 14 doses were completed by 10/14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhoea) occurred in 8 participants (57.1%), with urine and sclera discolouration 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 first dose and maintained throughout. Nitazoxanide administered at 1500mg BID with food was safe with acceptable tolerability a phase 1b/2a study is now being initiated in COVID-19 patients.
Keywords: COVID-19; Coronavirus; Pharmacokinetics; Phase I; Repurposing; SARS-CoV-2.
. 2021 Oct 26.
doi: 10.1002/cpt.2463. Online ahead of print.
An open label, adaptive, phase 1 trial of high-dose oral nitazoxanide in healthy volunteers: an antiviral candidate for SARS-CoV-2
Lauren E Walker[SUP] 1 2 [/SUP], Richard FitzGerald[SUP] 2 [/SUP], Geoffrey Saunders[SUP] 3 [/SUP], Rebecca Lyon[SUP] 2 [/SUP], Michael Fisher[SUP] 1 2 [/SUP], Karen Martin[SUP] 3 [/SUP], Izabela Eberhart[SUP] 3 [/SUP], Christie Woods[SUP] 2 [/SUP], Sean Ewings[SUP] 3 [/SUP], Colin Hale[SUP] 2 [/SUP], Rajith Kr Rajoli[SUP] 1 [/SUP], Laura Else[SUP] 1 [/SUP], Sujan Dilly-Penchala[SUP] 1 [/SUP], Alieu Amara[SUP] 1 [/SUP], David G Lalloo[SUP] 4 [/SUP], Michael Jacobs[SUP] 4 [/SUP], Henry Pertinez[SUP] 1 [/SUP], Parys Hatchard[SUP] 3 [/SUP], Robert Waugh[SUP] 3 [/SUP], Megan Lawrence[SUP] 3 [/SUP], Lucy Johnson[SUP] 3 [/SUP], Keira Fines[SUP] 3 [/SUP], Helen Reynolds[SUP] 1 [/SUP], Timothy Rowland[SUP] 2 [/SUP], Rebecca Crook[SUP] 2 [/SUP], Emmanuel Okenyi[SUP] 2 [/SUP], Kelly Byrne[SUP] 4 [/SUP], Pavel Mozgunov[SUP] 5 [/SUP], Thomas Jaki[SUP] 5 [/SUP], Saye Khoo[SUP] 1 [/SUP], Andrew Owen[SUP] 1 [/SUP], Gareth Griffiths[SUP] 3 [/SUP], Thomas E Fletcher[SUP] 2 4 [/SUP], AGILE platform
Affiliations
- PMID: 34699618
- DOI: 10.1002/cpt.2463
Abstract
Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe 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 an FDA approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modelling 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 1 trial in healthy adult participants was undertaken with high dose nitazoxanide. Participants received 1500mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose and schedule. Intensive pharmacokinetic sampling was undertaken day 1 and 5 with Cmin sampling on day 3 and 7. Fourteen healthy participants were enrolled between 18[SUP]th[/SUP] February and 11[SUP]th[/SUP] May 2021. All 14 doses were completed by 10/14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhoea) occurred in 8 participants (57.1%), with urine and sclera discolouration 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 first dose and maintained throughout. Nitazoxanide administered at 1500mg BID with food was safe with acceptable tolerability a phase 1b/2a study is now being initiated in COVID-19 patients.
Keywords: COVID-19; Coronavirus; Pharmacokinetics; Phase I; Repurposing; SARS-CoV-2.