Top

Breast Cancer Research and Treatment

Published in:

01-11-2019 | Breast Cancer | Epidemiology

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

Authors: Jin Young Moon, Ji Min Han, Inyoung Seo, Hye Sun Gwak

Published in: Breast Cancer Research and Treatment | Issue 1/2019

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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. https://doi.org/10.1200/JCO.2007.14.0590 CrossRefPubMed

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):434–438CrossRef

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):811–814CrossRef

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):177–182CrossRef

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. https://doi.org/10.1124/dmd.111.040949 CrossRefPubMed

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):6255–6263CrossRef

Shah RR, Morganroth J, Shah DR (2013) Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 36(7):491–503. https://doi.org/10.1007/s40264-013-0048-4 CrossRefPubMed

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. https://doi.org/10.1124/mol.110.065839 CrossRefPubMed

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. https://doi.org/10.1517/17425255.2015.983075 CrossRefPubMed

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. https://doi.org/10.1200/JCO.2010.31.3197 CrossRefPubMed

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. https://doi.org/10.1097/FPC.0b013e3283385a1c CrossRef

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. https://doi.org/10.1038/clpt.2012.73 CrossRefPubMed

13.

Walgren JL, Mitchell MD, Thompson DC (2008) Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 35(4):325–361CrossRef

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):367–377CrossRef

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. https://doi.org/10.1038/nrd3408 CrossRefPubMed

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. https://doi.org/10.1007/s11095-012-0724-6 CrossRefPubMed

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. https://doi.org/10.1124/dmd.116.070839 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1007/s10549-012-1995-7 CrossRefPubMed

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. https://doi.org/10.1111/j.1365-2125.2009.03370.x CrossRefPubMedPubMedCentral

Title: Risk factors associated with the incidence and time to onset of lapatinib-induced hepatotoxicity
Authors: Jin Young Moon
Ji Min Han
Inyoung Seo
Hye Sun Gwak
Publication date: 01-11-2019
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Lapatinib
Published in: Breast Cancer Research and Treatment / Issue 1/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05382-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Risk of malignancy in papillary neoplasms of the breast

Assessing the quality and communicative aspects of patient decision aids for early-stage breast cancer treatment: a systematic review

In BRCA mutation carriers breast conserving surgery may not be the best choice

Plasma cell-free DNA chromosomal instability analysis by low-pass whole-genome sequencing to monitor breast cancer relapse

PK-M2-mediated metabolic changes in breast cancer cells induced by ionizing radiation

National trends of synchronous bilateral breast cancer incidence in the United States

Keynote webinar | Spotlight on antibody–drug conjugates in cancer