Pharmacokinetics, Metabolism, and Partial Biodistribution of “Pincer Therapeutic” Nitazoxanide in Mice following Pulmonary Delivery of Inhalable Particles

Gupta, A.; Tulsankar, Sachin Laxman; Bhatta, Rabi Sankar; Misra, Amit

doi:10.1021/acs.molpharmaceut.6b01089

Cited by 13 publications

(8 citation statements)

References 19 publications

(40 reference statements)

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“…For this analysis, animal lung concentration data were available for anidulafungin (rat), bazedoxifene (rat), chloroquine (3 albino rat studies), favipiravir (monkey), hydroxychloroquine (2 albino rat studies), nitazoxanide (mouse), tamoxifen (rat), cyclosporine (rat), ritonavir (rat), azithromycin (mouse), dolutegravir (mouse), gilteritinib (albino rat), and lopinavir (rat). [23][24][25][26][27][28][29][30][31][32] Agreement between the predicted and measured K p was assessed by simple linear regression and by constructing Bland-Altman plots, the limits of agreement (mean ± 2 SD) were included in these plots as previously described. 33…”

Section: Data Analysis and Interpretationmentioning

confidence: 99%

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Clin Pharma and Therapeutics

137

148

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90) values recalculated from in vitro anti‐SARS‐CoV‐2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax/EC90 ratio above 1. A more in‐depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir‐boosted), and sulfadoxine achieved plasma concentrations above their reported anti‐SARS‐CoV‐2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated to derive a lung Cmax/half‐maximal effective concentration (EC50) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir‐boosted), tipranavir (ritonavir‐boosted), ivermectin, azithromycin, and lopinavir (ritonavir‐boosted) were all predicted to achieve lung concentrations over 10‐fold higher than their reported EC50. Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8‐fold and 1.5‐fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.

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Section: Data Analysis and Interpretationmentioning

confidence: 99%

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Clin Pharma and Therapeutics

137

148

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“…In a previous pharmacokinetic study of NTZ in mice, optimal concentrations of TIZ were obtained in the lungs when the molecule was entrapped in inhalable particles. 43 This type of formulation combined with aerosol administration could potentially lead to an effective concentration of NTZ in the animal's lungs and deserves further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…In conclusion, optimization of the NTZ formulation may allow reconsideration of the potential use of the drug for the treatment of SARS-CoV-2 infection. In a previous pharmacokinetic study of NTZ in mice, optimal concentrations of TIZ were obtained in the lungs when the molecule was entrapped in inhalable particles (34). This type of formulation combined with aerosol administration could potentially lead to an effective concentration of NTZ in the animal’s lungs and deserves further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

Driouich

Cochin

Touret

et al. 2021

Preprint

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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.

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Pharmacokinetics, Metabolism, and Partial Biodistribution of “Pincer Therapeutic” Nitazoxanide in Mice following Pulmonary Delivery of Inhalable Particles

Cited by 13 publications

References 19 publications

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

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

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

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