Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model

  1. J. Errecalde
  2. A. Lifschitz
  3. G. Vecchioli
  4. L. Ceballos
  5. F. Errecalde
  6. M. Ballent
  7. G. Marín
  8. M. Daniele
  9. E. Turic
  10. E. Spitzer
  11. F. Toneguzzo
  12. S. Gold
  13. A. Krolewiecki
  14. L. Alvarez
  15. C. Lanusse

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Abstract

High ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray (N-IVM-spray) administration may contribute to attaining high drug concentrations in nasopharyngeal (NP) tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performance of a new N-IVM spray formulation in a piglet model were assessed. Crossbred piglets (10–12 kg) were treated with either one or two (12 h apart) doses of N-IVM-spray (2 mg, 1 puff/nostril) or orally (0.2 mg/kg). The overall safety of N-IVM-spray was assessed (clinical, haematological, serum biochemical determinations), and histopathology evaluation of the application site tissues performed. The IVM concentration profiles measured in plasma and respiratory tract tissues (nasopharynx and lungs) after the nasal spray treatment (one and two applications) were compared with those achieved after the oral administration. Animals tolerated well the novel N–IVM-spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in NP and lung tissues. Significant increases in IVM concentration profiles in both NP-tissue and lungs were observed after the 2-dose nasal administrations. The nasal/oral IVM concentration ratios in NP and lung tissues (at 6 h post-dose) markedely increased by repeating the spray application. The fast attainment of high and persistent IVM concentrations in NP tissue is the main advantage of the nasal over the oral route. These original results are encouraging to support the undertaking of further clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the treatment and/or prevention of COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.23.352831: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was fully performed in compliance with ethical, animal procedures and management protocols approved by the Ethics Committee on Animal Welfare Policy of Biogenesis Bago, Argentina (Pol-UE 0001).
    RandomizationBlood, nasopharyngeal and lung tissues sampling for drug measurement: Four (4) animals from each of the experimental groups were randomly selected to be euthanized at each sampling time following approved animal guidelines.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The statistical analysis was performed using the Instat 3.0 software (GraphPad Software, CA, US).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results 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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.10.23.352831v1 on bioRxiv