Association between high serum favipiravir concentrations and drug-induced liver injury

  1. Hitoshi Kawasuji
  2. Yasuhiro Tsuji
  3. Chika Ogami
  4. Yusuke Takegoshi
  5. Makito Kaneda
  6. Yushi Murai
  7. Kou Kimoto
  8. Akitoshi Ueno
  9. Yuki Miyajima
  10. Yasutaka Fukui
  11. Kentaro Nagaoka
  12. Ippei Sakamaki
  13. Yoshitomo Morinaga
  14. Yoshihiro Yamamoto

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Abstract

Objectives

This study aimed to evaluate the incidence and pattern of favipiravir-induced liver injury and the potential association between serum concentrations in hospitalized COVID-19 patients.

Patients and methods

We retrospectively reviewed laboratory-confirmed patients with COVID-19 for whom serum favipiravir trough concentration ( C min ) was measured under steady-state conditions during treatment. All patients were administered 1800 mg of favipiravir twice daily on the first day and 800 mg twice daily from the second day.

Results

Thirty observed favipiravir concentrations were collected from nine patients. Of these, favipiravir-induced liver injury developed in three patients after 13 (11–14) days from the initiation of therapy, with two classified as cholestatic and one hepatocellular injury, with a score of four (possible), seven (probable), and three (possible) based on the CIMOS/RUCAM scoring system. Median (range) favipiravir C min at steady state was found to be significantly higher in patients with liver injury at 66.4 (47.8–72.4) mg/L than in those without injury at 12.8 (9.4–21.8) mg/L ( P = 0.028).

Conclusions

Higher favipiravir serum concentrations were observed in patients who developed favipiravir-induced liver injury than in those who did not. As the variations in favipiravir concentrations between patients were large, personalized optimal dosing strategies may be needed for safe use.

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  1. ScreenIT

    SciScore for 10.1101/2021.05.03.21256437: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: 2.6 Ethics approval: This study was performed as per the Declaration of Helsinki and was approved by the Ethical Review Board of the University of Toyama (approval numbers: R2019167 and R2020146) and Nihon University (School of Pharmacy, approval number: 20-005).
    Consent: Written informed consent was obtained from all patients.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data were analyzed using JMP Pro version 15.0.0 software (SAS Institute Inc.
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    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:
    The number of patients involved was quite small, which was a limitation of this study. Thus, representativeness is relatively insufficient, and the samples can only represent the general situation to a certain extent. However, our findings indicate a difference in serum favipiravir concentrations between patients with and without favipiravir-induced liver injury. Additionally, large variations in favipiravir concentrations were observed (steady-state Cmin: 3.1–72.4 mg/L) in this study of patients without renal and underlying hepatic impairment. The Cmin values in patient 3 decreased from 115.5 (55.5–144.8) mg/L to 5.4 (3.8–44.6) mg/L after introducing CHDF. Although the influence of continuous renal replacement therapy (CRRT) on the clearance of favipiravir is unclear, this case suggests that evaluating the influence of CRRT could be significant for considering the optimum dose of favipiravir. These findings indicate that a pharmacokinetic multinational study should be performed with larger samples to reveal the significant covariates and elucidate the potentially exposure-dependent favipiravir-induced liver injury.

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2021.05.03.21256437 on medRxiv