Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers

  1. Y. A. de Reus
  2. P. Hagedoorn
  3. M. G. G. Sturkenboom
  4. F. Grasmeijer
  5. M. S. Bolhuis
  6. I. Sibum
  7. H. A. M. Kerstjens
  8. H. W. Frijlink
  9. O. W. Akkerman

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.

Objectives

To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.

Methods

Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.

Results and discussion

Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV 1 post inhalation. The serum HCQ concentration remained below 10 μg/L in all samples.

Conclusion

Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted.

Article activity feed

  1. Version published to 10.1371/journal.pone.0272034
  2. ScreenIT

    SciScore for 10.1101/2020.12.03.20243162: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the local medical ethical review committee (METc UMCG, Groningen, The Netherlands, METc number 2020.168).
    Consent: The study was conducted with the written informed consent of all participating subjects.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Training was done using an empty Cyclops connected to a laptop, with in-house developed software application (labVIEW, National Instruments, the Netherlands) for recording of and processing of flow curves generated through the device.
    labVIEW
    suggested: (LabView , RRID:SCR_014325)
    Data management and statistics: Study data were collected and managed using Research Electronic Data Capture (REDCap) [40, 41].
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    Statistical analysis was performed with SPSS version 23.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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 our study is that only serum concentrations are measured and not local pulmonary concentrations. So far, only in vitro experiments on Vero cells have shown efficacy and data from human pulmonary concentrations and thus local efficacy are lacking [8, 9]. Since in our study no systemic exposure of HCQ was detected for all participants and for all doses, it is not expected that systemic side effects will occur and HCQ might therefore also be used in patients of older age and with comorbidities. In conclusion, HCQ inhalation using the Cyclops is safe and generally well tolerated by healthy volunteers, except for minor cough and bitter taste. These positive results and the superior safety and efficacy potential of inhaled over oral HCQ strongly encourage the execution of further clinical studies with inhaled HCQ to battle this COVID-19 pandemic.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04497519CompletedLocal Tolerability and Pharmacokinetic Evaluation of Cyclops…

    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.

  3. Version published to 10.1101/2020.12.03.20243162v1 on medRxiv