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Disproportionality analysis of acetaminophen-induced hepatic disorders with and without immune checkpoint inhibitors

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Abstract

Background

Although acetaminophen is recommended for the treatment of mild-to-moderate cancer pain, acetaminophen-induced hepatic disorders pose an important clinical challenge. Concomitant prescription of immune checkpoint inhibitors (ICIs) may further increase the risk of hepatic disorders in patients taking acetaminophen; however, there are few clinical studies that confirm this.

Aim

To evaluate the risk of hepatic disorders in patients taking concomitant acetaminophen and ICIs using a disproportionality analysis from the Japanese Adverse Drug Event Report database.

Method

Acetaminophen users aged ≥ 20 years were included; factors that can affect the risk of acetaminophen-induced hepatic disorders were collated. Similar data on the widely used analgesic, loxoprofen, were used for comparison.

Results

Among 233,594 patients surveyed, 10,403 were prescribed acetaminophen, and among them, 1,245 patients developed hepatic disorders. The disproportionality of hepatic disorders was observed in acetaminophen users regardless of concomitant ICI use (without ICI: reporting odds ratio [ROR], 1.18; 95% confidence intervals [CI], 1.10–1.26; with ICI: ROR 1.87, 95%CI 1.59–2.20); it was even higher in concomitant acetaminophen and ICI users (ROR 1.94, 95%CI 1.65–2.29). However, increased disproportionality of hepatic disorders was not observed in patients taking concomitant loxoprofen and ICI. Multivariable logistic regression showed that the risk of hepatic disorders in acetaminophen users was associated with concomitant use of ICI (ROR, 1.91; 95% CI, 1.49–2.45); (P < 0.01).

Conclusion

Our findings suggest that the risk of hepatic disorders is greater with concomitant acetaminophen and ICI treatment than with acetaminophen alone.

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References

  1. Aminoshariae A, Khan A. Acetaminophen: old drug, new issues. J Endod. 2015;41:588–93. https://doi.org/10.1016/j.joen.2015.01.024.

    Article  PubMed  Google Scholar 

  2. WHO. WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. https://www.who.int/publications/i/item/9789241550390. Accessed 01 Jan  2022.

  3. Ishitsuka Y, Kondo Y, Kadowaki D. Toxicological property of acetaminophen: the dark side of a safe antipyretic/analgesic drug? Biol Pharm Bull. 2020;43:195–206. https://doi.org/10.1248/bpb.b19-00722.

    Article  CAS  PubMed  Google Scholar 

  4. Ramachandran A, Jaeschke H. Acetaminophen hepatotoxicity. Semin Liver Dis. 2019;39:221–34. https://doi.org/10.1055/s-0039-1679919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yan M, Huo Y, Yin S, et al. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol. 2018;17:274–83. https://doi.org/10.1016/j.redox.2018.04.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jaeschke H, Ramachandran A. Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity. Food Chem Toxicol. 2020;138:111240. https://doi.org/10.1016/j.fct.2020.111240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Noda T, Kato R, Hattori T, et al. Role of caspase-8 and/or – 9 as biomarkers that can distinguish the potential to cause toxic- and immune related-adverse event, for the progress of acetaminophen-induced liver injury. Life Sci. 2022;294:120351. https://doi.org/10.1016/j.lfs.2022.120351.

    Article  CAS  PubMed  Google Scholar 

  8. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36:1714–68. https://doi.org/10.1200/JCO.2017.77.6385.

    Article  CAS  PubMed  Google Scholar 

  9. Thompson JA. New NCCN guidelines: recognition and management of immunotherapy-related toxicity. J Natl Compr Canc Netw. 2018;16:594–96. https://doi.org/10.6004/jnccn.2018.0047.

    Article  PubMed  Google Scholar 

  10. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. https://doi.org/10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cho T, Kok LY, Uetrecht J. Testing possible risk factors for idiosyncratic drug-induced liver injury using an amodiaquine mouse model and co-treatment with 1-methyl-d-tryptophan or acetaminophen. ACS Omega. 2021;6:4656–62. https://doi.org/10.1021/acsomega.0c05352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pharmaceuticals and Medical Devices Agency. http://www.pmda.go.jp/. Accessed  07 Nov  2021.

  13. Corcoran GB, Wong BK. Obesity as a risk factor in drug-induced organ injury: increased liver and kidney damage by acetaminophen in the obese overfed rat. J Pharmacol Exp Ther. 1987;241:921–27.

    CAS  PubMed  Google Scholar 

  14. Michaut A, Moreau C, Robin MA, et al. Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease. Liver Int. 2014;34:e171-79. https://doi.org/10.1111/liv.12514.

    Article  CAS  PubMed  Google Scholar 

  15. Nguyen GC, Sam J, Thuluvath PJ. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis. Hepatology. 2008;48:1336–41. https://doi.org/10.1002/hep.22536.

    Article  CAS  PubMed  Google Scholar 

  16. Tsumura H, Tamura I, Tanaka H, et al. Prescription of nonsteroidal anti-inflammatory drugs and co-prescribed drugs for mucosal protection: analysis of the present status based on questionnaires obtained from orthopedists in Japan. Intern Med. 2007;46:927–31. https://doi.org/10.2169/internalmedicine.46.0003.

    Article  PubMed  Google Scholar 

  17. Pharmaceutical and Medical Device Regulatory Science Society of Japan. MedDRA Japanese maintenance organization. https://www.jmo.pmrj.jp/. Accessed 02 May 2022.

  18. FDA. Drug development and drug interactions. Table of substrates, inhibitors and inducers; 2019. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Accessed 02 May 2022.

  19. Guggenheimer J, Moore PA. The therapeutic applications of and risks associated with acetaminophen use: a review and update. J Am Dent Assoc. 2011;142:38–44. https://doi.org/10.14219/jada.archive.2011.0026.

    Article  PubMed  Google Scholar 

  20. Japan Society for the study of obesity (JASSO). Guidelines for the management of obesity disease. Tokyo: Life Science Publishing Co, Ltd; 2016.

  21. AYUMI Pharmaceutical Corporation. CALONAL Package Inesrt Jpn. 2021.

  22. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD index 2022. https://www.whocc.no/atc_ddd_index/. Accessed 12 May 2022.

  23. Cho YA, Han JM, Kang SY, et al. Analysis of risk factors for hepatotoxicity induced by immune checkpoint inhibitors. J Immunother. 2021;44:16–21. https://doi.org/10.1097/CJI.0000000000000347.

    Article  CAS  PubMed  Google Scholar 

  24. Greig SL, Garnock-Jones KP. Loxoprofen: a review in pain and inflammation. Clin Drug Investig. 2016;36:771–81. https://doi.org/10.1007/s40261-016-0440-9.

    Article  CAS  PubMed  Google Scholar 

  25. Aiso M, Takikawa H, Tsuji K, et al. Analysis of 307 cases with drug-induced liver injury between 2010 and 2018 in Japan. Hepatol Res. 2019;49:105–10. https://doi.org/10.1111/hepr.13288.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Editage (https://www.editage.jp/) provided assistance in the preparation of this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pharmacy, Osaka Medical and Pharmaceutical University Hospital, 2–7, Daigaku-machi, Takatsuki, Osaka, 569–8686, Japan

    Tomoyuki Yamada PhD, Masami Nishihara BSc & Masashi Neo MD, PhD

  2. Department of Cardiovascular Pharmacotherapy and Toxicology, Osaka Medical and Pharmaceutical University, 4-20-1, Nasahara, Takatsuki, Osaka, 569–1094, Japan

    Ryuji Kato PhD & Yoshio Ijiri PhD

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  1. Tomoyuki Yamada PhD
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  2. Ryuji Kato PhD
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Correspondence to Tomoyuki Yamada PhD.

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Yamada, T., Kato, R., Ijiri, Y. et al. Disproportionality analysis of acetaminophen-induced hepatic disorders with and without immune checkpoint inhibitors. Int J Clin Pharm 45, 442–450 (2023). https://doi.org/10.1007/s11096-022-01527-z

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  • DOI: https://doi.org/10.1007/s11096-022-01527-z

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