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Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study

  • Pharmacoepidemiology and Prescription
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I–II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III–IV) hepatotoxicity of TKIs.

Methods

This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively.

Results

Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255–3.944) and 3.3-fold (95% CI 1.260–8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561–7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106–0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers.

Conclusion

The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files (Online Resource 2).

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Acknowledgments

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Author notes

  1. Ji Min Han and Hye Won Han contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, South Korea

    Ji Min Han, Hye Won Han, Jeong Yee, Jin Young Moon, Soyeon Cho & Hye Sun Gwak

  2. Department of Pharmacy, Seoul National University Hospital, Seoul, 03080, South Korea

    Ji Min Han, Min Kyoung Kim & Yoon Sook Cho

  3. Department of Pharmacy, Asan Medical Center, Seoul, 05505, South Korea

    Hye Won Han, Soyeon Cho, Dasom Jung & Jae Youn Kim

  4. Graduate School of Converging Clinical & Public Health, Ewha Womans University, Seoul, 03760, South Korea

    Min Kyoung Kim & Dasom Jung

  5. Department of Pharmacy, National Cancer Center, Goyang-si, 10408, South Korea

    Jin Young Moon & Inyoung Seo

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  1. Ji Min Han
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Contributions

JMH, HWH and HSG contributed to the study conception and design. Material preparation and data collection were performed by JMH, HWH, MKK, JYM, SC, and DJ. Data analysis and interpretation were performed by JMH, HWH, JY, YSC, IS, and JYK. The manuscript was written by JMH and HWH. The manuscript was revised by HSG. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Hye Sun Gwak.

Ethics declarations

All procedures performed in five studies involving human participants were in accordance with the ethical standards of the relevant ethics committees, which approved the studies, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The requirement for obtaining informed consent was waived due to the retrospective nature of this study.

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The authors declare that they have no conflict of interest.

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Han, J.M., Han, H.W., Yee, J. et al. Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study. Eur J Clin Pharmacol 76, 1183–1191 (2020). https://doi.org/10.1007/s00228-020-02897-x

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  • DOI: https://doi.org/10.1007/s00228-020-02897-x

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