Dose prediction for repurposing nitazoxanide in SARS‐CoV‐2 treatment or chemoprophylaxis
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS‐CoV‐2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS‐CoV‐2 EC 90 .
Methods
A whole‐body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC 90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.
Results
The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated.
Conclusion
The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS‐CoV‐2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.
Article activity feed
-
-
SciScore for 10.1101/2020.05.01.20087130: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Effective permeability (Peff) in humans was scaled from apparent permeability (Papp) in HT29-19A cells (due to lack of available data, it was assumed the same in Caco-2 cells) using the following equations to compute the rate of absorption (Ka in h-1) from the small intestine. HT29-19Asuggested: RRID:CVCL_0323)Caco-2suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing …SciScore for 10.1101/2020.05.01.20087130: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Effective permeability (Peff) in humans was scaled from apparent permeability (Papp) in HT29-19A cells (due to lack of available data, it was assumed the same in Caco-2 cells) using the following equations to compute the rate of absorption (Ka in h-1) from the small intestine. HT29-19Asuggested: RRID:CVCL_0323)Caco-2suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, there are some important limitations that must be considered. PBPK models can be useful in dose prediction but the quality of predictions is only as good as the quality of the available data on which they are based. Furthermore, the mechanism of action for nitazoxanide for other viruses has also been postulated to involve an indirect mechanism through amplification of the host innate immune response [59], and this would not have been captured in the in vitro antiviral activity that informed the target concentrations for this dose prediction. The simulated population used in this modelling consisted of healthy individuals up to 60 years old, but many patients requiring therapy may be older and have underlying comorbidities. To best knowledge, the impact of renal and hepatic impairment on pharmacokinetics of this drug have not been assessed and may impact the pharmacokinetics. Although the current PBPK model is validated against various single doses in the fasted state and few multiple doses when given with food, the model may predict with less accuracy for multiple doses due to the unavailability of clinical data for multiple dosing over 1000 mg. The presented models were validated using BID doses only, and confidence in the predictions for TID and QID doses may be lower. The clinical studies used for model validation were performed in a limited number of patients [29] and thus may underrepresent real inter-subject variability. Also, the disposition parameters (appare...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04341493 Recruiting Hydroxychloroquine vs Nitazoxanide in Patients With COVID-19 NCT01227421 Completed Safety and Efficacy Study of Nitazoxanide in the Treatment o… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
