Pre-clinical evaluation of antiviral activity of nitazoxanide against Sars-CoV-2

Abstract

To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.

Calpain-2 mediates SARS-CoV-2 entry and represents a therapeutic target

“…1 ). Nitazoxanide was recently reported to inhibit SARS-CoV-2 infection [9] and we observed similar results ( Fig. S1 ).…”

Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey

“…In fact, only one preprint posted in December 2021 claimed that both NTZ and TIZ show similar antiviral results in Vero E6 and Caco-2 cells [178].…”

“…In February 2020, Wang and colleagues confirmed that NTZ was able to inhibit the novel coronavirus at low micromolar concentrations (IC 50 = 2.12 μM; CC 50 > 35.53 μM), although the antiviral potency of the active metabolite TIZ was absent from the study [ 42 ]. In fact, only one preprint posted in December 2021 claimed that both NTZ and TIZ show similar antiviral results in Vero E6 and Caco-2 cells [ 178 ].…”