A Strategy to Treat COVID‐19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study

  1. Tien‐Tzu Tai
  2. Tzung‐Ju Wu
  3. Huey‐Dong Wu
  4. Yi‐Chen Tsai
  5. Hui‐Ting Wang
  6. An‐Min Wang
  7. Sheue‐Fang Shih
  8. Yee‐Chun Chen

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a newly identified pathogen causing the coronavirus disease 2019 (COVID‐19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti‐inflammatory drug, has been shown to inhibit SARS‐CoV‐2 infection in vitro and tested in clinical studies. However, achievement of lung concentrations predicted to have in vivo antiviral efficacy might not be possible with the currently proposed oral dosing regimens. Further, high cumulative doses of HCQ raise concerns of systemic toxicity, including cardiotoxicity. Here, we describe a preclinical study to investigate the pharmacokinetics (PKs) of a novel formulation of liposomal HCQ administered by intratracheal (IT) instillation in Sprague‐Dawley rats. Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (~ 30‐fold) lung exposure, longer (~ 2.5‐fold) half‐life in lungs, but lower blood exposure with ~ 20% of peak plasma concentration (C max ) and 74% of area under the curve from 0 to 72 hours (AUC 0–72 ) and lower heart exposure with 23% of C max and 58% of AUC 0–24 (normalized for dose). Similar results were observed relative to IT administration of unformulated HCQ. These PKs result in an animal model that demonstrated the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID‐19.

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  1. Version published to 10.1111/cts.12923
  2. ScreenIT

    SciScore for 10.1101/2020.07.09.196618: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: All procedures involving animals were performed in TLC animal facility and in accordance with the ethical guidelines of Institutional Animal Care and Use Committee (IACUC) at TLC, Taiwan (#TLC20IACUC012).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableStudy Design: A total of 52 female SD rats (BioLASCO Taiwan Co., Ltd.) were assigned to one of three treatment groups: (1) HCQ-IV: 12 rats received a single dose of 0.590 mg HCQ sulfate per animal via IV injection; (2) HCQ-IT: 20 rats received a single dose of 0.590 mg HCQ sulfate per animal via intratracheal (IT) administration; and (3) liposomal HCQ-IT: 20 rats received a single dose of 0.284 mg liposomal HCQ sulfate per animal via IT administration.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    PK parameters of HCQ were calculated by a non-compartmental method using Phoenix® WinNonlin® (version 8.0).
    Phoenix®
    suggested: (Phoenix, RRID:SCR_003163)
    WinNonlin®
    suggested: None

    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: We detected the following sentences addressing limitations in the study:
    A limitation of the current study is that the pharmacokinetics of liposomal HCQ were evaluated in a rat model using IT instillation to mimic the intended inhalation administration. The typical lung deposition efficiency with inhaled aerosols is very likely lower than that of the IT instilled microsprayed-droplets. Furthermore, it is suggested the aerosol-generating procedure (nebulization) on patients with known or suspected COVID-19 should be performed cautiously given that SARS-CoV-2 is highly contagious through the respiratory route (https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html) (15). Therefore, we have developed a disposable closed-loop system connected to the nebulizer to maximize the targeted delivery of inhaled liposomal HCQ while minimize the spreading and contaminating the air and environment (data not shown). In conclusion, this study in a rat model demonstrate the desirable pharmacokinetics of inhalable liposomal HCQ in vivo. It supports the working hypothesis that inhalable liposomal HCQ might serve as a potential treatment option for the delivery of HCQ for COVID-19 pulmonary disease by achieving targeted antiviral levels with less frequent dosing and at a relatively lower dose.

    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:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • 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

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  3. Version published to 10.1101/2020.07.09.196618v1 on bioRxiv