 |
|
|
| |
Phase 1 Trial Suggests Antidiarrheal Nitazoxanide Dose for COVID
|
| |
| |
International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs, September 20-22, 2021
By Mark Mascolini for NATAP and Virology Education
Nitazoxanide, an antiparasitic used to treat diarrhea in people at least 1 year old, should be studied at a dose of 1500 mg twice daily in people infected with SARS-CoV-2, according to results of a small open-label trial in healthy UK adults [1]. That's 3 times the dose approved for diarrhea in people without COVID-19 [2].
A broad-spectrum thiazolide antiparasitic, nitazoxanide is licensed in the United States and elsewhere for treatment of cryptosporidiosis (Cryptosporidium parvum) and giardiasis (Giardia duodenalis) infections in people at least 1 year old [2]. Although used as an antiparasitic, nitazoxanide is active in lab studies against a range of viruses, including influenza viruses, hepatitis B and C, norovirus, rotavirus, Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 [2]. Researchers believe nitazoxanide could stall SARS-CoV-2 replication by preventing maturation of the viral spike protein, essential for docking on target cells.
Right now the US COVID-19 Treatment Guidelines Panel recommends against using nitazoxanide for COVID-19, except in clinical trials. That advice rests on results of two randomized controlled trials in Brazil [3] and the US [4] that found no solid evidence of nitazoxanide efficacy against SARS-CoV-2 in nonhospitalized adults, The US trial did find that nitazoxanide prevented worsening of mild or moderate COVID-19 [4], but the US COVID-19 treatment panel believes the trial did not have the statistical power to support that conclusion [2]. The nitazoxanide doses used in these trials were 500 mg 3 times daily for 5 days [3] and 600 mg in 2 extended-release tablets twice daily [4]. Single doses of nitazoxanide up to 4000 mg have been studied in humans [5]. At the dose approved for diarrhea, the researchers noted nitazoxanide has an "exemplary" safety record.
The UK AGILE platform aims to hasten study of agents potentially useful against COVID-19 [6]. As part of that effort, University of Liverpool researchers and colleagues at other centers conducted an open-label, adaptive, phase 1 trial in healthy adults [1]. The research team noted that nitazoxanide attains maximum concentrations above the lab-determined target at the standard dose of 500 twice daily. But physiologically based pharmacokinetic (PBPK) modeling indicates that much higher doses are needed to sustain antiviral minimum concentrations (Cmin).
Healthy men and women 18 to 75 years old were eligible for this trial of nitazoxanide at 1500 mg twice daily with food for 7 days. Depending on results with that dose, the trial could go on to test 1000 mg 3 times daily or 1500 mg in the morning and 2000 mg at night. The researchers collected intensive samples to measure nitazoxanide levels on days 1 and 5. They collected samples to measure Cmin on days 3 and 7.
Fourteen recruited participants had a median age of 25 (range 19 to 53), 9 (64%) were women, 12 (86%) were white, and 2 (14%) were Asian. Median body mass index stood at 23.9 kg/m2 (range 19.3 to 30.8).
All 14 volunteers took at least 1 dose, and 10 took all 14 planned doses. The investigators temporarily paused the trial when suspected QT prolongation (a possible harbinger of rapid heart beat) appeared in 1 participant. As a result of cohort stopping criteria, 4 people stopped treatment after this possible QT episode. The trial resumed when independent manual reading of the electrocardiogram attributed the suspected heart rhythm problem to fusion of the T and the U waves.
All other adverse events were mild or moderate in these people taking 1500 mg of nitazoxanide twice daily for 7 days. Three of 14 people (21%) had moderate gastrointestinal complaints and 8 (57%) had mild gastrointestinal problems (nausea, bloating, constipation, diarrhea, loose stools, abdominal pain). Twelve participants (86%) had discolored urine and 9 (64%) had discolored sclera (the white of the eyeball), but none of them had significantly high bilirubin. This discoloration cleared up when people stopped taking nitazoxanide.
Nitazoxanide blood levels confirmed the PBPK modeling prediction on treatment day 1, but modeling underpredicted drug exposure on day 5. After the first dose of nitazoxanide, median Cmin lay above the lab-defined target concentration and remained above the target throughout treatment.
Of the three potential nitazoxanide doses considered in this study, 1500 mg twice daily struck the best balance between probability of reaching the target concentration and probability of avoiding toxicity. Therefore the trial's Safety Review Committee picked this dose to evaluate in a phase 1b/2a trial starting in South Africans with acute SARS-CoV-2 infection.
References
1. Walker L, FitzGerald R, Saunders G, et al. An open label, adaptive, phase 1 trial of high-dose oral nitazoxanide in healthy volunteers: an antiviral candidate for treatment of COVID-19. International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs 2021. September 20-22, 2021. Abstract 2.
2. National Institutes of Health. COVID-19 Guidelines. Nitazoxanide.
https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/nitazoxanide/
3. Rocco PRM, Silvia PL, Cruz FF, et al. Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial. Eur Respir J. 2021. Published online ahead of print. https://www.ncbi.nlm.nih.gov/pubmed/33361100.
4. Rossignol J, Bardin MC, Oaks JB, et al. Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent hospitalization. medRxiv. 2021. Preprint. https://www.medrxiv.org/content/10.1101/2021.04.19.21255441v1.
5. Stockis A, Alleman AM, De Bruyn S, Gengler C. Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses. Int J Clin Pharmacol Ther. 2002;40:213-220.
6. ClinicalTrials.gov. AGILE (Early Phase Platform Trial for COVID-19). ClinicalTrials.gov identifier NCT04746183.
|
| |
|
|
|
|
|
