Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Drug Safety
Published in: Drug Safety 7/2013

01-07-2013 | Review Article

Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives

Authors: Rashmi R. Shah, Joel Morganroth, Devron R. Shah

Published in: Drug Safety | Issue 7/2013

Login to get access

Abstract

The introduction of small-molecule tyrosine kinase inhibitors (TKIs) in clinical oncology has transformed the treatment of certain forms of cancers. As of 31 March 2013, 18 such agents have been approved by the US Food and Drug Administration (FDA), 15 of these also by the European Medicines Agency (EMA), and a large number of others are in development or under regulatory review. Unexpectedly, however, their use has been found to be associated with serious toxic effects on a number of vital organs including the liver. Drug-induced hepatotoxicity has resulted in withdrawal from the market of many widely used drugs and is a major public health issue that continues to concern all the stakeholders. This review focuses on hepatotoxic potential of TKIs. The majority of TKIs approved to date are reported to induce hepatic injury. Five of these (lapatinib, pazopanib, ponatinib, regorafenib and sunitinib) are sufficiently potent in this respect as to require a boxed label warning. Onset of TKI-induced hepatotoxicity is usually within the first 2 months of initiating treatment, but may be delayed, and is usually reversible. Fatality from TKI-induced hepatotoxicity is uncommon compared to hepatotoxic drugs in other classes but may lead to long-term consequences such as cirrhosis. Patients should be carefully monitored for TKI-induced hepatotoxicity, the management of which requires individually tailored reappraisal of the risk/benefit. The risk is usually manageable by dose adjustment or a switch to a suitable alternative TKI. Confirmation of TKI-induced hepatotoxicity can present challenges in the presence of hepatic metastasis and potential drug interactions. Its diagnosis in a patient with TKI-sensitive cancer requires great care if therapy with the TKI suspected to be causal is to be modified or interrupted as a result. Post-marketing experience with drugs such as imatinib, lapatinib and sorafenib suggests that the hepatotoxic safety of all the TKIs requires diligent surveillance.
Literature
1.
Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172–87.PubMedCrossRef
2.
Chen MH, Kerkela R, Force T. Mechanisms of cardiomyopathy associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118:84–95.PubMedCrossRef
3.
Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29:2543–9.PubMedCrossRef
4.
Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarization (QT interval). Drug Saf. 2013. doi:10.​1007/​s40264-013-0047-5.
5.
6.
Seruga B, Sterling L, Wang L, et al. Reporting of serious adverse drug reactions of targeted anticancer agents in pivotal phase III clinical trials. J Clin Oncol. 2011;29:174–85.PubMedCrossRef
7.
Niraula S, Seruga B, Ocana A, et al. The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs. J Clin Oncol. 2012;30:3012–9.PubMedCrossRef
8.
Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42:481–9.PubMedCrossRef
9.
Andrade RJ, Lucena MI, Fernández MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish Registry over a 10-year period. Gastroenterology 2005;129:512–21. Erratum in: Gastroenterology. 2005;129:1808.
10.
Shah RR. Drug-induced hepatotoxicity: pharmacokinetic perspectives and strategies for risk reduction. Advers Drug React Toxicol Rev. 1999;18:181–233.
11.
Srivastava A, Maggs JL, Antoine DJ, et al. Role of reactive metabolites in drug-induced hepatotoxicity. Handb Exp Pharmacol. 2010;196:165–94.PubMedCrossRef
12.
Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16:3041–53.PubMedCrossRef
13.
Andrade RJ, Robles M, Ulzurrun E, et al. Drug-induced liver injury: insights from genetic studies. Pharmacogenomics. 2009;10:1467–87.PubMedCrossRef
14.
Bessone F. Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage? World J Gastroenterol. 2010;16:5651–61.PubMedCrossRef
15.
Russmann S, Jetter A, Kullak-Ublick GA. Pharmacogenetics of drug-induced liver injury. Hepatology. 2010;52:748–61.PubMedCrossRef
16.
Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol. 2011;8:202–11.PubMedCrossRef
17.
Ju C, Reilly T. Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev. 2012;44:107–15.PubMedCrossRef
18.
Pessayre D, Fromenty B, Berson A, et al. Central role of mitochondria in drug-induced liver injury. Drug Metab Rev. 2012;44:34–87.PubMedCrossRef
19.
Spriet-Pourra C, Auriche M. Drug withdrawal from sale. Scrip reports. Richmond: PJB; 1994.
20.
Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics. 2006;7:889–908.PubMedCrossRef
21.
Chalasani N, Björnsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology. 2010;138:2246–59.PubMedCrossRef
22.
Daly AK, Donaldson PT, Bhatnagar P, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41:816–9.PubMedCrossRef
23.
Zimmerman HJ, Lewis JH, Ishak KG, et al. Ticrynafen-associated hepatic injury: analysis of 340 cases. Hepatology. 1984;4:315–23.PubMedCrossRef
24.
Graham DJ, Drinkard CR, Shatin D, et al. Liver enzyme monitoring in patients treated with troglitazone. JAMA. 2001;286:831–3.PubMedCrossRef
25.
Graham DJ, Green L, Senior JR, et al. Troglitazone-induced liver failure: a case study. Am J Med. 2003;114:299–306.PubMedCrossRef
26.
27.
28.
29.
30.
31.
Lewis JH. The adaptive response (drug tolerance) helps to prevent drug-induced liver injury. Gastroenterol Hepat (NY). 2012;8:333–6.
32.
Eder JP, Shapiro GI, Appleman LJ, et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res. 2010;16:3507–16.PubMedCrossRef
33.
Feng B, Xu JJ, Bi YA, et al. Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714. Toxicol Sci. 2009;108:492–500.PubMedCrossRef
34.
Munster PN, Britten CD, Mita M, et al. First study of the safety, tolerability, and pharmacokinetics of CP-724,714 in patients with advanced malignant solid HER2-expressing tumors. Clin Cancer Res. 2007;13:1238–45.PubMedCrossRef
35.
Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. Cancer Treat Rev. 2013;39:199–206.PubMedCrossRef
36.
37.
Spataro V. Nilotinib in a patient with postnecrotic liver cirrhosis related to imatinib. J Clin Oncol. 2011;29:e50–2.PubMedCrossRef
38.
Ridruejo E, Cacchione R, Villamil AG, et al. Imatinib-induced fatal acute liver failure. World J Gastroenterol. 2007;13:6608–11.PubMed
39.
Kong JH, Yoo SH, Lee KE, et al. Early imatinib-mesylate-induced hepatotoxicity in chronic myelogenous leukaemia. Acta Haematol. 2007;118:205–8.PubMedCrossRef
40.
Pariente A, Etcharry F, Cales V, et al. Imatinib mesylate-induced acute hepatitis in a patient treated for gastrointestinal stromal tumour. Eur J Gastroenterol Hepatol. 2006;18:785–7.PubMedCrossRef
41.
Fuster F, Medina L, Vallansot R, et al. Imatinib-induced toxic hepatitis: description of two cases and review of the literature. Artic Span Gastroenterol Hepatol. 2007;30:525–30.CrossRef
42.
Tonyali O, Coskun U, Yildiz R, et al. Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors. Med Oncol. 2010;27:768–73.PubMedCrossRef
43.
Weise AM, Liu CY, Shields AF. Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine. Ann Pharmacother. 2009;43:761–6.PubMedCrossRef
44.
45.
46.
Takeda M, Okamoto I, Fukuoka M, et al. Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity. J Clin Oncol. 2010;28:e273–4.PubMedCrossRef
47.
Seki N, Uematsu K, Shibakuki R, et al. Promising new treatment schedule for gefitinib responders after severe hepatotoxicity with daily administration. J Clin Oncol. 2006;24:3213–4.PubMedCrossRef
48.
Kijima T, Shimizu T, Nonen S, et al. Safe and successful treatment with erlotinib after gefitinib-induced hepatotoxicity: difference in metabolism as a possible mechanism. J Clin Oncol. 2011;29:e588–90.PubMedCrossRef
49.
Lim SY, Ando S, Nishiyama K, et al. Multiple myeloma emerging after prolonged gefitinib treatment for non-small cell lung carcinoma. Case Rep Oncol. 2011;4:198–203.PubMedCrossRef
50.
Spraggs CF, Budde LR, Briley LP, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011;29:667–73.PubMedCrossRef
51.
Suzumura T, Kimura T, Kudoh S, et al. Comparison of adverse events of erlotinib with those of gefitinib in patients with non-small cell lung cancer: a case-control study in a Japanese population. Osaka City Med J. 2012;58:25–34.PubMed
52.
Suzumura T, Kimura T, Kudoh S, et al. Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer. BMC Cancer. 2012;12:568.PubMedCrossRef
53.
Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98:1714–23.PubMedCrossRef
54.
Donahower B, McCullough SS, Kurten R, et al. Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity. Am J Physiol Gastrointest Liver Physiol. 2006;291:G102–9.PubMedCrossRef
55.
Wang T, Shankar K, Ronis MJ, et al. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Crit Rev Toxicol. 2007;37:413–59.PubMedCrossRef
56.
Nakagawa H, Maeda S, Hikiba Y, et al. Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology. 2008;135:1311–21.PubMedCrossRef
57.
Revuelta-Cervantes J, Mayoral R, Miranda S, et al. Protein tyrosine phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice. Am J Pathol. 2011;178:1591–604.PubMedCrossRef
58.
Han D, Shinohara M, Ybanez MD, et al. Signal transduction pathways involved in drug-induced liver injury. Handb Exp Pharmacol. 2010;196:267–310.PubMedCrossRef
59.
Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–9.PubMedCrossRef
60.
Llanos L, Bellot P, Zapater P, et al. Acute hepatitis in a patient with cirrhosis and hepatocellular carcinoma treated with sorafenib. Am J Gastroenterol. 2009;104:257–8.PubMedCrossRef
61.
Fairfax B, Pratap S, Roberts I, et al. Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma. BMC Cancer. 2012;12:590.PubMedCrossRef
62.
Herden U, Fischer L, Schafer H, et al. Sorafenib-induced severe acute hepatitis in a stable liver transplant recipient. Transplantation. 2010;90:98–9.PubMedCrossRef
63.
Schramm C, Schuch G, Lohse AW. Sorafenib-induced liver failure. Am J Gastroenterol. 2008;103:2162–3.PubMedCrossRef
64.
Marks AB, Gerard R, Fournier P, et al. Sorafenib-induced hepatic encephalopathy. Ann Pharmacother. 2009;43:2121.PubMedCrossRef
65.
Van Hootegem A, Verslype A, Van Steenbergen W. Sorafenib-induced liver failure: a case report and review of the literature. Case Rep Hepatol. 2011; Article ID 941395, 4 pp.
66.
67.
Xu C-F, Reck BH, Xue Z, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert’s syndrome UGT1A1 polymorphism. Br J Cancer. 2010;102:1371–7.PubMedCrossRef
68.
69.
Mandery K, Glaeser H, Fromm MF. Interaction of innovative small molecule drugs used for cancer therapy with drug transporters. Br J Pharmacol. 2012;165:345–62.PubMedCrossRef
70.
Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117:e75–87.PubMedCrossRef
71.
Court MH, Duan SX, von Moltke LL, et al. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther. 2001;299:998–1006.PubMed
72.
Mutlib AE, Goosen TC, Bauman JN, et al. Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chem Res Toxicol. 2006;19:701–9.PubMedCrossRef
73.
Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol. 1980;10(Suppl 2):291S–8S.PubMedCrossRef
74.
75.
Kostrubsky SE, Sinclair JF, Strom SC, et al. Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci. 2005;87:146–55.PubMedCrossRef
76.
Liu Y, Ramirez J, House L, et al. Comparison of the drug-drug interactions potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. Drug Metab Dispos. 2010;38:32–9.PubMedCrossRef
77.
Liu Y, Ramírez J, Ratain MJ. Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. Br J Clin Pharmacol. 2011;71:917–20.PubMedCrossRef
78.
Laine JE, Auriola S, Pasanen M, et al. Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica. 2009;39:11–21.PubMedCrossRef
79.
80.
81.
Nassar I, Pasupati T, Judson JP, et al. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model. Malays J Pathol. 2010;32:1–11.PubMed
82.
Kim DW, Tan EY, Jin Y, et al. Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia. Br J Clin Pharmacol. 2011;71:199–206.PubMedCrossRef
83.
Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367–73.PubMedCrossRef
84.
Lim AYL, Segarra I, Chakravarthi S, et al. Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice. BMC Pharmacol. 2010;10:14.PubMedCrossRef
85.
Ohashi Y, Suzuki K, Sakurai M, et al. Safety analysis of eight patients treated with erlotinib after severe gefitinib-induced liver injury. Gan To Kagaku Ryoho. 2010;37:1307–11. (Article in Japanese).PubMed
86.
Ku GY, Chopra A. Lopes Gde L Jr. Successful treatment of two lung cancer patients with erlotinib following gefitinib-induced hepatotoxicity. Lung Cancer. 2010;70:223–5.PubMedCrossRef
87.
Nagano T, Kotani Y, Kobayashi K, et al. Successful erlotinib treatment for a patient with gefitinib-related hepatotoxicity and lung adenocarcinoma refractory to intermittently administered gefitinib. Case Rep Pulmonol. 2011;2011:812972.PubMed
88.
Kitade H, Yamada T, Igarashi S, et al. Efficacy of low-dose erlotinib against gefitinib-induced hepatotoxicity in a patient with lung adenocarcinoma harboring EGFR mutations. Gan To Kagaku Ryoho. 2013;40:79–81. (Article in Japanese).PubMed
89.
Takeda M, Okamoto I, Tsurutani J, et al. Clinical impact of switching to a second EGFR-TKI after a severe AE related to a first EGFR-TKI in EGFR-mutated NSCLC. Jpn J Clin Oncol. 2012;42:528–33.PubMedCrossRef
90.
Nakatomi K, Nakamura Y, Tetsuya I, et al. Treatment with gefitinib after erlotinib-induced liver injury: a case report. J Med Case Rep. 2011;5:593.PubMedCrossRef
91.
Kunimasa K, Yoshioka H, Iwasaku M, et al. Successful treatment of non-small cell lung cancer with gefitinib after severe erlotinib-related hepatotoxicity. Intern Med. 2012;51:431–4.PubMedCrossRef
92.
Chang SC, Chang CY, Chen CY, et al. Successful erlotinib rechallenge after gefitinib-induced acute interstitial pneumonia. J Thorac Oncol. 2010;5:1105–6.PubMedCrossRef
93.
Fukui T, Otani S, Hataishi R, et al. Successful rechallenge with erlotinib in a patient with EGFR-mutant lung adenocarcinoma who developed gefitinib-related interstitial lung disease. Cancer Chemother Pharmacol. 2010;65:803–6.PubMedCrossRef
94.
Koma Y, Matsuoka H, Yoshimatsu H, et al. Successful treatment with erlotinib after gefitinib-induced interstitial lung disease: a case report and literature review. Int J Clin Pharmacol Ther. 2012;50:760–4.PubMed
95.
Tammaro KA, Baldwin PD, Lundberg AS. Interstitial lung disease following erlotinib (Tarceva) in a patient who previously tolerated gefitinib (Iressa). J Oncol Pharm Pract. 2005;11:127–30.PubMedCrossRef
96.
Lin NU, Sarantopoulos S, Stone JR, et al. Fatal hepatic necrosis following imatinib mesylate therapy. Blood. 2003;102:3455–6.PubMedCrossRef
97.
Kikuchi S, Muroi K, Takahashi S, et al. Severe hepatitis and complete molecular response caused by imatinib mesylate: possible association of its serum concentration with clinical outcomes. Leuk Lymphoma. 2004;45:2349–51.PubMedCrossRef
98.
Cross TJ, Bagot C, Portmann B, et al. Imatinib mesylate as a cause of acute liver failure. Am J Hematol. 2006;81:189–92.PubMedCrossRef
99.
James C, Trouette H, Marit G, et al. Histological features of acute hepatitis after imatinib mesylate treatment. Leukemia. 2003;17:978–9.PubMedCrossRef
100.
Ohyashiki K, Kuriyama Y, Nakajima A, et al. Imatinib mesylate-induced hepatotoxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis. Leukemia. 2002;16:2160–1.PubMedCrossRef
101.
Saif MW. Erlotinib-induced acute hepatitis in a patient with pancreatic cancer. Clin Adv Hematol Oncol. 2008;6:191–9.PubMed
102.
Ho C, Davis J, Anderson F, et al. Side effects related to cancer treatment: hepatitis following treatment with gefitinib. J Clin Oncol. 2005;23:8531–3.PubMedCrossRef
Metadata
Title
Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives
Authors
Rashmi R. Shah
Joel Morganroth
Devron R. Shah
Publication date
01-07-2013
Publisher
Springer International Publishing AG
Published in
Drug Safety / Issue 7/2013
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI
https://doi.org/10.1007/s40264-013-0048-4

Other articles of this Issue 7/2013

Drug Safety 7/2013 Go to the issue

Original Research Article

A Potential Event-Competition Bias in Safety Signal Detection: Results from a Spontaneous Reporting Research Database in France

Short Communication

Probabilistic Record Linkage for Monitoring the Safety of Artemisinin-Based Combination Therapy in the First Trimester of Pregnancy in Senegal

Erratum

Erratum to: Characterization of Statin-Associated Myopathy Case Reports in Thailand Using the Health Product Vigilance Center Database

Original Research Article

Data Mining for Prospective Early Detection of Safety Signals in the Vaccine Adverse Event Reporting System (VAERS): A Case Study of Febrile Seizures after a 2010–2011 Seasonal Influenza Virus Vaccine

Original Research Article

The Impact of Direct Healthcare Professional Communication on Prescribing Practice in the UK Hospital Setting: An Interrupted Time Series Analysis

Original Research Article

Implementing Ecopharmacovigilance in Practice: Challenges and Potential Opportunities