Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

  1. Catia Marzolini
  2. Felix Stader
  3. Marcel Stoeckle
  4. Fabian Franzeck
  5. Adrian Egli
  6. Stefano Bassetti
  7. Alexa Hollinger
  8. Michael Osthoff
  9. Maja Weisser
  10. Caroline E. Gebhard
  11. Veronika Baettig
  12. Julia Geenen
  13. Nina Khanna
  14. Sarah Tschudin-Sutter
  15. Daniel Mueller
  16. Hans H. Hirsch
  17. Manuel Battegay
  18. Parham Sendi

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Abstract

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7.

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  1. Version published to 10.1128/aac.01177-20
  2. ScreenIT

    SciScore for 10.1101/2020.07.05.20146878: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was part of a COVID-19 cohort consortium investigation and approved by the northwest/central Switzerland Ethics Committee (EKNZ 2020-00769).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All statistical analyses were performed with GraphPad Prism and SPSS.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    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:
    Some limitations of this study should be acknowledged. We did not consider IL-6 measurement as a routine diagnostic value within our COVID-19 cohort, and hence, in study. IL-6 is a central mediator of the acute-phase response and a primary determinant of hepatic production of CRP. IL-6 has many other pathophysiologic roles in humans (42) and its diagnostic value for COVID-19, in particular for non-severe cases, is unknown. The selection of cutoff of 12 hours in the case of TCZ administration prior to measurement of LPV plasma concentrations was clinically reasonable but arbitrary. However, this limitation applied to only 3 patients, and had no statistical influence on the results. In conclusion, high LPV trough plasma concentrations were observed in COVID-19 patients. However, the calculated unbound concentrations in the lung indicates insufficient levels to inhibit SARS-CoV-2 replication. LPV levels correlated positively with CRP values and negatively with the preadministration of TCZ, indicating that COVID-19 related cytokine release significantly inhibits CYP3A4. Caution is advised when prescribing CYP3A4 substrates with a narrow therapeutic index to COVID-19 patients because of the risk of elevated drug levels and related toxicities.

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

    IdentifierStatusTitle
    NCT04351503RecruitingA Systems Approach to Predict the Outcome of SARS-CoV-2 in t…

    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.
    • Thank you for including a protocol registration statement.

    About SciScore

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  3. Version published to 10.1101/2020.07.05.20146878v1 on medRxiv