Breast Cancer Research and Treatment

, Volume 178, Issue 1, pp 239–244 | Cite as

Risk factors associated with the incidence and time to onset of lapatinib-induced hepatotoxicity

  • Jin Young Moon
  • Ji Min Han
  • Inyoung Seo
  • Hye Sun GwakEmail author



Although lapatinib-induced hepatotoxicity can cause severe clinical complications in patients, the factors affecting hepatotoxicity have rarely been investigated. The purpose of this study was to investigate risk factors for hepatotoxicity and time to lapatinib-induced hepatotoxicity.


This retrospective study was performed on metastatic breast cancer patients treated with lapatinib. Various factors were evaluated for hepatotoxicity and time to hepatotoxicity, including sex, age, body weight, height, body surface area, underlying disease, smoking history, start dose of lapatinib, status of liver metastasis, and concomitant drugs.


Among 159 patients, the percentage of patients with hepatotoxicity after lapatinib initiation was 57.9% (n = 92). Multivariate analysis showed that concomitant use of H2 blockers increased the incidence of hepatotoxicity by 2.3-fold. Patients who received CYP3A4 inducers had 3.1 times higher risk of hepatotoxicity incidence; the attributable risks of H2 blockers and CYP3A4 inducers were 56.7% and 68.1%, respectively. Use of H2 blockers increased the hazard of time to hepatotoxicity by 1.8-fold compared to non-use of H2 blockers.


Our study demonstrated that concomitant use of H2 blockers and CYP3A4 inducers was associated with lapatinib-induced hepatotoxicity. Close liver function monitoring is recommended, especially in patients receiving H2 blockers or CYP3A4 inducers.


Lapatinib Hepatotoxicity H2 blocker CYP3A4 inducer 


Author contribution

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

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

This study was approved by the Institutional Review Board of National Cancer Center, Korea (IRB number: NCC 2019-0091), and the requirement for obtaining informed consent was waived due to the retrospective nature of this study.


  1. 1.
    Gomez HL, Doval DC, Chavez MA et al (2008) Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 26(18):2999–3005. CrossRefPubMedGoogle Scholar
  2. 2.
    Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL, Altman DG (1991) c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 63(3):434–438CrossRefGoogle Scholar
  3. 3.
    Nicholson S, Wright C, Sainsbury JR et al (1990) Epidermal growth factor receptor (EGFr) as a marker for poor prognosis in node-negative breast cancer patients: neu and tamoxifen failure. J Steroid Biochem Mol Biol 37(6):811–814CrossRefGoogle Scholar
  4. 4.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182CrossRefGoogle Scholar
  5. 5.
    Castellino S, O’Mara M, Koch K, Borts DJ, Bowers GD, MacLauchlin C (2012) Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab Dispos 40(1):139–150. CrossRefPubMedGoogle Scholar
  6. 6.
    Xia W, Mullin RJ, Keith BR et al (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21(41):6255–6263CrossRefGoogle Scholar
  7. 7.
    Shah RR, Morganroth J, Shah DR (2013) Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 36(7):491–503. CrossRefPubMedGoogle Scholar
  8. 8.
    Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, Chan EC (2010) Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol 78(4):693–703. CrossRefPubMedGoogle Scholar
  9. 9.
    Teo YL, Ho HK, Chan A (2015) Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review. Expert Opin Drug Metab Toxicol 11(2):231–242. CrossRefPubMedGoogle Scholar
  10. 10.
    Spraggs CF, Budde LR, Briley LP et al (2011) HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 29(6):667–673. CrossRefPubMedGoogle Scholar
  11. 11.
    Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB (2011) Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genom 21(3):152–161. CrossRefGoogle Scholar
  12. 12.
    Budha NR, Frymoyer A, Smelick GS et al (2012) Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther 92(2):203–213. CrossRefPubMedGoogle Scholar
  13. 13.
    Walgren JL, Mitchell MD, Thompson DC (2008) Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 35(4):325–361CrossRefGoogle Scholar
  14. 14.
    Ju C, Uetrecht JP (2002) Mechanism of idiosyncratic drug reactions: reactive metabolites formation, protein binding and the regulation of the immune system. Curr Drug Metab 3(4):367–377CrossRefGoogle Scholar
  15. 15.
    Park BK, Boobis A, Clarke S et al (2011) Managing the challenge of chemically reactive metabolites in drug development. Nat Rev Drug Discov 10(4):292–306. CrossRefPubMedGoogle Scholar
  16. 16.
    Kenny JR, Mukadam S, Zhang C, Tay S, Collins C, Galetin A, Khojasteh SC (2012) Drug–drug interaction potential of marketed oncology drugs: in vitro assessment of time-dependent cytochrome P450 inhibition, reactive metabolite formation and drug–drug interaction prediction. Pharm Res 29(7):1960–1976. CrossRefPubMedGoogle Scholar
  17. 17.
    Towles JK, Clark RN, Wahlin MD, Uttamsingh V, Rettie AE, Jackson KD (2016) Cytochrome P450 3A4 and CYP3A5-catalyzed bioactivation of lapatinib. Drug Metab Dispos 44(10):1584–1597. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Teo YL, Saetaew M, Chanthawong S, Yap YS, Chan EC, Ho HK, Chan A (2012) Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: clinical and in vitro evidence. Breast Cancer Res Treat 133(2):703–711. CrossRefPubMedGoogle Scholar
  19. 19.
    Smith DA, Koch KM, Arya N, Bowen CJ, Herendeen JM, Beelen A (2009) Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. Br J Clin Pharmacol 67(4):421–426. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of Pharmacy and Division of Life and Pharmaceutical SciencesEwha Womans UniversitySeoulSouth Korea
  2. 2.Department of PharmacyNational Cancer CenterGoyang-siSouth Korea

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