Plasma Concentrations and Safety of Lopinavir/Ritonavir in COVID-19 Patients

  1. Laurent Chouchana
  2. Sana Boujaafar
  3. Ines Gana
  4. Laure-Hélène Preta
  5. Lucile Regard
  6. Paul Legendre
  7. Celia Azoulay
  8. Etienne Canouï
  9. Jeremie Zerbit
  10. Nicolas Carlier
  11. Benjamin Terrier
  12. Solen Kernéis
  13. Rui Batista
  14. Jean-Marc Treluyer
  15. Yi Zheng
  16. Sihem Benaboud

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Abstract

Although the efficacy of lopinavir/ritonavir has not been proven, it has been proposed as an off-label treatment for COVID-19. Previously, it has been reported that the plasma concentrations of lopinavir significantly increase in inflammatory settings. As COVID-19 may be associated with major inflammation, assessing the plasma concentrations and safety of lopinavir in COVID-19 patients is essential.

Methods:

Real-world COVID-19 data based on a retrospective study.

Results:

Among the 31 COVID-19 patients treated with lopinavir/ritonavir between March 18, 2020 and April 1, 2020, higher lopinavir plasma concentrations were observed, which increased by 4.6-fold (interquartile range: 3.6–6.2), compared with the average plasma concentrations in HIV. Lopinavir concentrations in all except one patient were above the upper limit of the concentration range of HIV treatment. Approximately one to 5 patients prematurely stopped treatment mainly because of an ADR related to hepatic or gastrointestinal disorders.

Conclusions:

Lopinavir plasma concentrations in patients with moderate-to-severe COVID-19 were higher than expected, and they were associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, a high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2, as suggested by previous studies. Therefore, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Caution is essential because off-label use can be associated with a new drug safety profile.

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  1. Version published to 10.1097/ftd.0000000000000838
  2. Version published to 10.1101/2020.05.18.20105650v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2020.05.18.20105650: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study has been performed in accordance with the declaration of Helsinki and received approval by the Cochin Hospital Institutional Review Board (number 2020-08019).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    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:
    Our study has several limitations. First, due to the retrospective design using data from routine care, plasma assays were drawn at different times that prevent from an accurate pharmacokinetic estimation. Second, according to different practices in wards, Covid-19 severity at baseline was heterogeneous between patients. However, most importantly, in all assayed patients, LPV plasma concentrations regardless assays timing were unexpectedly high comparing HIV experience. Finally, unbound concentrations, which are the active ones, were not estimated.

    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.

  4. Version published to 10.1101/2020.05.18.20105650v1 on medRxiv