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Remdesivir Discontinuation Decisions Based on Thresholds of Aminotransferase in an Observational Registry

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Abstract

Background

Remdesivir is an antiviral approved by the US Food and Drug Administration (FDA) for treatment of coronavirus disease 2019 (COVID-19), and aminotransferase elevation is commonly reported. Thresholds to be considered for discontinuation due to alanine aminotransferase (ALT) elevation differ between the FDA and European Medicines Agency (EMA). The primary objective was to describe aminotransferase thresholds being used in real-world practice for discontinuation of remdesivir in patients with COVID-19, and compare them with labeled recommendations.

Methods

This study used a descriptive design based on an ongoing national registry of adverse events, the FDA ACMT COVID-19 ToxIC (FACT) pharmacovigilance project, with 17 participating health systems in the USA. Cases were identified retrospectively for an 18-month period (23 November 2020–18 May 2022). Classification of discontinuation as premature and due to aminotransferases was based on chart documentation by the treating team.

Results

Of 1026 cases in the FACT registry, 116 cases were included with supplemental data forms completed for aminotransferase elevation with remdesivir, defined a priori for inclusion as ALT doubling or increasing by ≥ 50 U/L. ALT was elevated prior to remdesivir in 47% and increased above baseline during dosing by a median of 92 U/L [interquartile range (IQR) 51–164, max 8350]. Remdesivir was discontinued early in 37 (31.9%) patients due to elevated aminotransferases. The ALT threshold for premature discontinuation was median 200 U/L (IQR 145–396, range 92–5743). Among patients with premature discontinuation of remdesivir for aminotransferase elevation, only 21.6% met FDA criteria to consider discontinuation, and 40.5% met prior EMA criteria to consider discontinuation.

Conclusion

In this descriptive study of real-world practice in the USA, clinicians are overall making more conservative treatment decisions than are recommended for consideration in approved drug labeling of discontinuation, with wide variation in the aminotransferase thresholds being used.

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References

  1. FDA Approved Labeling. Veklury (remdesivir). Highlights of prescribing information. Revised: 06/2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214787Orig1s015lbl.pdf.

  2. FDA Approved Labeling. Olumiant (baricitinib). Highlights of prescribing information. Revised: 05/2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207924s006lbl.pdf. 2022.

  3. U.S. Food & Drug Administration. Coronavirus (COVID-19) | Drugs. https://www.fda.gov/drugs/emergency-preparedness-drugs/coronavirus-covid-19-drugs.

  4. U.S. Food & Drug Administration. Fact sheet for health care providers: Emergency Use Authorization (EUA) of Veklury® (remdesivir). August 2020. https://www.fda.gov/media/143189/download.

  5. Gilead. Veklury: Annex I: summary of product characteristics. Revised June 2023. https://veklury.eu/ie/media_uploads/2023/07/UK-Ireland-Malta-Veklury-SmPC-PDF-1.pdf.

  6. European Medicines Agency. Remdesivir: Annex I: summary of product characteristics. March 28, 2022. https://www.ema.europa.eu/en/documents/product-information/veklury-epar-product-information_en.pdf.

  7. Wax PM, Aldy K, Brent J. Rapid development of the FDA ACMT COVID-19 ToxIC (FACT) pharmacovigilance pilot project to monitor adverse events reported in association with COVID-19 therapeutics. Toxicol Lett. 2021;350:S20.

  8. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, Initiative S. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4(10): e296. https://doi.org/10.1371/journal.pmed.0040296.

    Article  Google Scholar 

  9. Jacob L, Smith L, Armstrong N, Yakkundi A, Barnett Y, Butler L, et al. Alcohol use and mental health during COVID-19 lockdown: a cross-sectional study in a sample of UK adults. Drug Alcohol Depend. 2021;219:108488.

  10. Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–15.

    Article  CAS  PubMed  Google Scholar 

  11. Hundt MA, Deng Y, Ciarleglio MM, Nathanson MH, Lim JK. Abnormal liver tests in COVID-19: a retrospective observational cohort study of 1,827 patients in a major US hospital network. Hepatology. 2020;72(4):1169–76.

    Article  CAS  PubMed  Google Scholar 

  12. Bertolini A, van de Peppel IP, Bodewes F, Moshage H, Fantin A, Farinati F, et al. Abnormal liver function tests in patients with COVID-19: relevance and potential pathogenesis. Hepatology. 2020;72(5):1864–72.

    Article  CAS  PubMed  Google Scholar 

  13. Puelles VG, Lutgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383(6):590–2.

    Article  Google Scholar 

  14. Yip TC, Lui GC, Wong VW, Chow VC, Ho TH, Li TC, et al. Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19. Gut. 2021;70(4):733–42. https://doi.org/10.1136/gutjnl-2020-321726.

    Article  CAS  PubMed  Google Scholar 

  15. Jorgensen SCJ, Kebriaei R, Dresser LD. Remdesivir: review of pharmacology, pre-clinical data, and emerging clinical experience for COVID-19. Pharmacotherapy. 2020;40(7):659–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Durante-Mangoni E, Andini R, Bertolino L, Mele F, Florio LL, Murino P, et al. Early experience with remdesivir in SARS-CoV-2 pneumonia. Infection. 2020;48(5):779–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zampino R, Mele F, Florio LL, Bertolino L, Andini R, Galdo M, et al. Liver injury in remdesivir-treated COVID-19 patients. Hepatol Int. 2020;14(5):881–3.

    Article  PubMed  Google Scholar 

  18. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020;383(19):1813–26.

    Article  CAS  PubMed  Google Scholar 

  19. Carothers C, Birrer K, Vo M. Acetylcysteine for the treatment of suspected remdesivir-associated acute liver failure in COVID-19: a case series. Pharmacotherapy. 2020;40(11):1166–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wong GL, Wong VW, Thompson A, Jia J, Hou J, Lesmana CRA, et al. Management of patients with liver derangement during the COVID-19 pandemic: an Asia-Pacific position statement. Lancet Gastroenterol Hepatol. 2020;5(8):776–87. https://doi.org/10.1016/S2468-1253(20)30190-4.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Montastruc F, Thuriot S, Durrieu G. Hepatic disorders with the use of remdesivir for coronavirus 2019. Clin Gastroenterol Hepatol. 2020;18(12):2835–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med. 2020;382(24):2327–36.

    Article  CAS  PubMed  Google Scholar 

  23. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020;383(19):1827–37.

    Article  CAS  PubMed  Google Scholar 

  25. Antinori S, Cossu MV, Ridolfo AL, Rech R, Bonazzetti C, Pagani G, et al. Compassionate remdesivir treatment of severe COVID-19 pneumonia in intensive care unit (ICU) and non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status. Pharmacol Res. 2020;158: 104899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. U.S. Food & Drug Administration. FDA news release: coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment. May 1, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment.

  28. U.S. Food & Drug Administration. FDA news release: FDA approves first treatment for COVID-19. Oct 22, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19.

  29. Spinner CD, Gottlieb RL, Criner GJ, Arribas Lopez JR, Cattelan AM, Soriano Viladomiu A, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048–57.

    Article  CAS  PubMed  Google Scholar 

  30. Consortium WHOST, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed antiviral drugs for Covid-19—interim WHO solidarity trial results. N Engl J Med. 2021;384(6):497–511.

    Article  Google Scholar 

  31. Ali K, Azher T, Baqi M, Binnie A, Borgia S, Carrier FM, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ. 2022;194(7):E242–51.

    Article  CAS  PubMed  Google Scholar 

  32. Feng JY, Xu Y, Barauskas O, Perry JK, Ahmadyar S, Stepan G, et al. Role of mitochondrial RNA polymerase in the toxicity of nucleotide inhibitors of hepatitis C virus. Antimicrob Agents Chemother. 2016;60(2):806–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bjork JA, Wallace KB. Remdesivir; molecular and functional measures of mitochondrial safety. Toxicol Appl Pharmacol. 2021;433: 115783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ambrus C, Bakos E, Sarkadi B, Ozvegy-Laczka C, Telbisz A. Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics. Sci Rep. 2021;11(1):17810.

    Article  CAS  PubMed Central  Google Scholar 

  36. Nies AT, Konig J, Hofmann U, Kolz C, Fromm MF, Schwab M. Interaction of remdesivir with clinically relevant hepatic drug uptake transporters. Pharmaceutics. 2021;13(3):369.

  37. Kock K, Ferslew BC, Netterberg I, Yang K, Urban TJ, Swaan PW, et al. Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4. Drug Metab Dispos. 2014;42(4):665–74.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Tillmann HL, Barnhart HX, Serrano J, Rockey DC. Novel approaches to causality adjudication in drug-induced liver disease. Curr Hepatol Rep. 2018;17(3):276–82. https://doi.org/10.1007/s11901-018-0416-8.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lim AK. Abnormal liver function tests associated with severe rhabdomyolysis. World J Gastroenterol. 2020;26(10):1020–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–20.

    Article  CAS  PubMed  Google Scholar 

  41. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.

    Article  CAS  PubMed  Google Scholar 

  42. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26(3):664–9.

    Article  CAS  PubMed  Google Scholar 

  43. Hayashi PH. Drug-induced liver injury network causality assessment: criteria and experience in the United States. Int J Mol Sci. 2016;17(2):201.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30.

    Article  CAS  PubMed  Google Scholar 

  45. Yan VC. Phosphoramidate prodrugs continue to deliver: the journey of remdesivir (GS-5734) from the liver to peripheral blood mononuclear cells. ACS Med Chem Lett. 2022;13(4):520–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sun D. Remdesivir for treatment of COVID-19: combination of pulmonary and iv administration may offer aditional benefit. AAPS J. 2020;22(4):77.

    Article  CAS  PubMed  Google Scholar 

  47. Monteil V, Dyczynski M, Lauschke VM, Kwon H, Wirnsberger G, Youhanna S, et al. Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection. EMBO Mol Med. 2021;13(1): e13426. https://doi.org/10.15252/emmm.202013426.

    Article  CAS  PubMed  Google Scholar 

  48. Yan VC, Muller FL. Why remdesivir failed: preclinical assumptions overestimate the clinical efficacy of remdesivir for COVID-19 and Ebola. Antimicrob Agents Chemother. 2021;65(10): e0111721.

    Article  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the FDA American College of Medical Toxicology (ACMT) COVID-19 Toxicology Investigators Consortium (ToxIC) (FACT) Study Group: Maryann Amirshahi, Katie Boyle, Jennifer Carey, Michael Chary, Jason Devgun, Kennon Heard, Robert Hendrickson, Ziad Kazzi, Eric Lavonas, Michael Brett Marlin, Travis Olives, Anthony Pizon, Tony Rianprakaisang, Kapil Sharma, Sophia Sheikh, Meghan Spyres, and Timothy Wiegand.

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Authors and Affiliations

  1. Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1620, New York, NY, 10029, USA

    Jonathan Schimmel

  2. Parkland Health and Hospital Systems, Dallas, TX, USA

    Lindsey Claire Epperson

  3. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Lindsey Claire Epperson & Paul Wax

  4. American College of Medical Toxicology, Phoenix, AZ, USA

    Kim Aldy & Paul Wax

  5. School of Medicine, University of Colorado, Aurora, CO, USA

    Jeffrey Brent

  6. Department of Emergency Medicine, Denver Health and Hospital Authority, Denver, CO, USA

    Jennie Buchanan

  7. Department of Emergency Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Michael Levine

  8. United States Food and Drug Administration, Rockville, MD, USA

    Keith Burkhart

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the Toxicology Investigators Consortium FACT Study Group

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Correspondence to Jonathan Schimmel.

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Funding

This study was supported by the US Food and Drug Administration (FDA), contract 75F40119D10031. This publication reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Conflict of interest

The authors have no competing interests to declare that are relevant to the content of this article.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Institutional Review Board

This project was deemed non-human subjects research by the Western Institutional Review Board (WIRB)-Copernicus Group Institutional Review Board (IRB) and exempted or approved by institutional IRBs at participating sites.

Author contributions

JS conceptualized the study, cleaned and analyzed the data, and drafted and revised the paper. LCE drafted and revised the paper. KA, PW, KB, and J Brent designed and implemented the registry database, and revised the paper. J Buchanan contributed to the registry and revised the paper. ML contributed to the registry and revised the paper.

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Schimmel, J., Epperson, L.C., Aldy, K. et al. Remdesivir Discontinuation Decisions Based on Thresholds of Aminotransferase in an Observational Registry. Drugs 84, 209–217 (2024). https://doi.org/10.1007/s40265-023-01981-7

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