778
Views
6
CrossRef citations to date
0
Altmetric
Review

Hepatotoxicity of FDA-approved small molecule kinase inhibitors

, , , , , & show all
Pages 335-348 | Received 30 Jun 2020, Accepted 17 Dec 2020, Published online: 27 Dec 2020

References

  • Roskoski R. A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol Res. 2015 Oct;100:1–23.
  • Ferguson FM, Gray NS. Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018 May;17(5):353–377.
  • Cohen P. Protein kinases—the major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002;1(4):309.
  • Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol Res. 2019 Jun;144:19–50.
  • Schöning V, Krähenbühl S, Drewe J. The hepatotoxic potential of protein kinase inhibitors predicted with Random Forest and Artificial Neural Networks. Toxicol Lett. 2018 Dec;15(299):145–148.
  • Watkins PB. Drug safety sciences and the bottleneck in drug development. Clin Pharmacol Ther. 2011 Jun;89(6):788–790.
  • Chen M, Zhang J, Wang Y, et al. The liver toxicity knowledge base: a systems approach to a complex end point. Clin Pharmacol Ther. 2013 May;93(5):409–412.
  • Verma S, Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury. Gut. 2009 Nov;58(11):1555–1564.
  • Weiler S, Merz M, Kullak-Ublick GA. Drug-induced liver injury: the dawn of biomarkers? F1000Prime Rep. 2015 Mar;3(7):34.
  • An DH. Update on drug-induced liver injury. J Clin Exp Hepatol. 2012 Sep;2(3):247–259.
  • Chen M, Suzuki A, Borlak J, et al. Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol. 2015 Aug;63(2):503–514.
  • Hoofnagle JH, Serrano J, Knoben JE, et al. LiverTox: a website on drug-induced liver injury. Hepatology. 2013 Mar;57(3):873–874.
  • Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Saf. 2007;30(4):277–294.
  • Ricart AD. Drug-induced liver injury in Oncology. Ann Oncol. 2017 Aug 1;28(8):2013–2020.
  • Chowdhury S, Sarkar RR. Comparison of human cell signaling pathway databases–evolution, drawbacks and challenges. Database (Oxford). 2015 Jan;28:bau126.
  • Shi Q, Yang X, Ren L, et al. Recent advances in understanding the hepatotoxicity associated with protein kinase inhibitors. Expert Opin Drug Metab Toxicol. 2020 Mar;16(3):217–226.
  • Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011 Jun;89(6):806–815.
  • Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013 Jul;36(7):491–503.
  • Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of canada clinical trials group. J Clin Oncol. 2007 May 20;25(15):1960–1966.
  • Saif MW. Erlotinib-induced acute hepatitis in a patient with pancreatic cancer. Clin Adv Hematol Oncol. 2008 Mar;6(3):191.
  • Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for hr-positive, advanced breast cancer. N Engl J Med. 2016 Nov 3;375(18):1738–1748.
  • Lin NU, Sarantopoulos S, Stone JR, et al. Fatal hepatic necrosis following imatinib mesylate therapy. Blood. 2003 Nov 1;102(9):3455–3456.
  • Rueff B, Benhamou JP. Acute hepatic necrosis and fulminant hepatic failure. Gut. 1973 Oct;14(10):805–815.
  • Peroukides S, Makatsoris T, Koutras A, et al. Lapatinib-induced hepatitis: a case report. World J Gastroenterol. 2011 May 14;17(18):2349.
  • Ripault MP, Pinzani V, Fayolle V, et al. Crizotinib-induced acute hepatitis: first case with relapse after reintroduction with reduced dose. Clin Res Hepatol Gastroenterol. 2013 Feb;37(1):e21–23.
  • Herden U, Fischer L, Schafer H, et al. Sorafenib-induced severe acute hepatitis in a stable liver transplant recipient. Transplantation. 2010 Jul 15;90(1):98–99.
  • Sacre A, Lanthier N, Dano H, et al. Regorafenib induced severe toxic hepatitis: characterization and discussion. Liver Int. 2016 Nov;36(11):1590–1594.
  • Klempner SJ, Choueiri TK, Yee E, et al. Severe pazopanib-induced hepatotoxicity: clinical and histologic course in two patients. J Clin Oncol. 2012 Sep 20;30(27):e264–268.
  • Ramanarayanan J, Scarpace SL. Acute drug induced hepatitis due to erlotinib. Jop. 2007 Jan 9;8(1):39–43.
  • Tonyali O, Coskun U, Yildiz R, et al. Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors. Med Oncol. 2010 Sep;27(3):768–773.
  • Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002 Mar 15;99(6):1928–1937.
  • Bhatty O, Selim M, Kassim T, et al. A Case of Imatinib-Induced Hepatitis. Cureus. 2017 Jun 1;9(6):e1302.
  • Mermershtain W, Lazarev I, Shani-Shrem N, et al. Fatal liver failure in a patient treated with sunitinib for renal cell carcinoma. Clin Genitourin Cancer. 2013 Mar;11(1):70–72.
  • Cross TJ, Bagot C, Portmann B, et al. Imatinib mesylate as a cause of acute liver failure. Am J Hematol. 2006 Mar;81(3):189–192.
  • Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008 Oct 10;26(29):4714–4719.
  • Kapadia S, Hapani S, Choueiri TK, et al. Risk of liver toxicity with the angiogenesis inhibitor pazopanib in cancer patients. Acta Oncol. 2013 Aug;52(6):1202–1212.
  • Piawah S, Hyland C, Umetsu SE, et al. A case report of vanishing bile duct syndrome after exposure to pexidartinib (PLX3397) and paclitaxel. NPJ Breast Cancer. 2019 Jun 14;5(1):17.
  • Reau NS, Jensen DM. Vanishing bile duct syndrome. Clin Liver Dis. 2008 Feb;12(1):203–217.
  • Nakanuma Y, Tsuneyama K, Harada K. Pathology and pathogenesis of intrahepatic bile duct loss. J Hepatobiliary Pancreat Surg. 2001;8(4):303–315.
  • Durand F, Valla D. Assessment of the prognosis of cirrhosis: child–pugh versus MELD. J Hepatol. 2005;42(1):S100–S107.
  • Spataro V. Nilotinib in a patient with postnecrotic liver cirrhosis related to imatinib. J Clin Oncol. 2011 Jan 20;29(3):e50–e52.
  • Yin OQ, Gallagher N, Tanaka C, et al. Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study. Clin Ther. 2009;31:2459–2469.
  • Narasimhan NI, Dorer DJ, Davis J, et al. Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol. 2014 Aug;74(2):341–348.
  • 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 Jan;104(1):257.
  • van Geel RM, Hendrikx JJ, Vahl JE, et al. Crizotinib-induced fatal fulminant liver failure. Lung Cancer. 2016 Mar;93:17–19.
  • Sato Y, Fujimoto D, Shibata Y, et al. Fulminant hepatitis following crizotinib administration for ALK-positive non-small-cell lung carcinoma. Jpn J Clin Oncol. 2014 Sep;44(9):872–875.
  • Adhikari N, Kumar P, Venkatesulu BP, et al. Crizotinib-induced fulminant hepatic failure: a rare adverse event. J Glob Oncol. 2018 Sep;4:1–4.
  • Liu W, Makrauer FL, Qamar AA, et al. Fulminant hepatic failure secondary to erlotinib. Clin Gastroenterol Hepatol. 2007 Aug;5(8):917–920.
  • Takeda M, Okamoto I, Fukuoka M, et al. Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity. J Clin Oncol. 2010 Jun 10;28(17):e273–274.
  • Ridruejo E, Cacchione R, Villamil AG, et al. Imatinib-induced fatal acute liver failure. World J Gastroenterol. 2007 Dec 28;13(48): 6608–6111.
  • Kang BW, Lee SJ, Moon JH, et al. Chronic myeloid leukemia patient manifesting fatal hepatitis B virus reactivation during treatment with imatinib rescued by liver transplantation: case report and literature review. Int J Hematol. 2009 Oct;90(3):383–387.
  • Peroukides S, Makatsoris T, Koutras A, et al. Lapatinib-induced hepatitis: a case report. World J Gastroenterol. 2011 May 14;17(18):2349–2352.
  • Kumamoto K, Endo S, Isohata N, et al. Pseudocirrhosis caused by regorafenib in an advanced rectal cancer patient with multiple liver metastases. Mol Clin Oncol. 2017 Jan;6(1):63–66.
  • Uetake H, Sugihara K, Muro K, et al. Clinical features of regorafenib-induced liver injury in Japanese patients from postmarketing experience. Clin Colorectal Cancer. 2018 Mar;17(1):e49–e58.
  • Mueller EW, Rockey ML, Rashkin MC. Sunitinib-related fulminant hepatic failure: case report and review of the literature. Pharmacotherapy. 2008 Aug;28(8):1066–1070.
  • Han D, Dara L, Win S, et al. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci. 2013 Apr;34(4):243–253.
  • Ali SE, Waddington JC, Park BK, et al. Definition of the chemical and immunological signals involved in drug-induced liver injury. Chem Res Toxicol. 2019 Nov 14;31(1):61–76.
  • Schwabe RF, Brenner DA. Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G583–589.
  • Iorga A, Dara L, Drug-Induced Liver KN. Injury: cascade of events leading to cell death, apoptosis or necrosis. Int J Mol Sci. 2017 May 9;18(5):1018.
  • Vilas-Boas V, Cooreman A, Gijbels E, et al. Primary hepatocytes and their cultures for the testing of drug-induced liver injury. Adv Pharmacol. 2019;85:1–30.
  • Laverty HG, Antoine DJ, Benson C, et al. The potential of cytokines as safety biomarkers for drug-induced liver injury. Eur J Clin Pharmacol. 2010 Oct;66(10):961–976.
  • Kamalian L, Chadwick AE, Bayliss M, et al. The utility of hepG2 cells to identify direct mitochondrial dysfunction in the absence of cell death. Toxicol In Vitro. 2015 Jun;29(4):732–740.
  • Mingard C, Paech F, Bouitbir J, et al. Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines. J Appl Toxicol. 2018 Mar;38(3):418–431.
  • Zhang J, Ren L, Yang X, et al. Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138–148.
  • Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013 Jul;58(1):388–396.
  • Hughes JD, Blagg J, Price DA, et al. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4872–4875.
  • Chen M, Bisgin H, Tong L, et al. Toward predictive models for drug-induced liver injury in humans: are we there yet? Biomark Med. 2014;8(2):201–213.
  • Chen M, Borlak J, Tong WA. Model to predict severity of drug-induced liver injury in humans. Hepatology. 2016 Sep;64(3):931–940.
  • Paludetto MN, Bijani C, Puisset F, et al. Metalloporphyrin-catalyzed oxidation of sunitinib and pazopanib, two anticancer tyrosine kinase inhibitors: evidence for new potentially toxic metabolites. J Med Chem. 2018 Sep 13;61(17):7849–7860.
  • Thakkar D, Kate AS. Update on metabolism of abemaciclib: in silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry. Drug Test Anal. 2020 Mar;12(3):331–342.
  • Li X, Kamenecka TM, Cameron MD. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. Chem Res Toxicol. 2009 Oct;22(10):1736–1742.
  • Li X, Kamenecka TM, Cameron MD. Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile. Drug Metab Dispos. 2010 Jul;38(7):1238–1245.
  • Teng WC, Oh JW, New LS, et al. Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693–703.
  • Teo YL, Ho HK, Chan A. Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review. Expert Opin Drug Metab Toxicol. 2015 Feb;11(2):231–242.
  • Chen CM, Wu WB, Chen JF, et al. Characterization of the in vitro metabolites of idelalisib in liver microsomes and interspecies comparison. J Pharm Biomed Anal. 2019 Jan;5(162):249–256.
  • Lin D, Kostov R, Huang JT, et al. Novel pathways of ponatinib disposition catalyzed by cyp1a1 involving generation of potentially toxic metabolites. J Pharmacol Exp Ther. 2017 Oct;363(1):12–19.
  • Manley PW. Investigations into the potential role of metabolites on the anti-leukemic activity of imatinib, nilotinib and midostaurin. Chimia (Aarau). 2019 Aug 21;73(7):561–570.
  • Li X, He Y, Ruiz CH, et al. Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathways. Drug Metab Dispos. 2009 Jun;37(6):1242–1250.
  • Lin D, Kostov R, Huang JT, et al. Novel pathways of ponatinib disposition catalyzed by cyp1a1 involving generation of potentially toxic metabolites. J Pharmacol Exp Ther. 2017 Oct;363(1):12–19.
  • Pan G. Roles of hepatic drug transporters in drug disposition and liver toxicity. Adv Exp Med Biol. 2019;1141:293–340.
  • Clinical Practice EASL. Guidelines: drug-induced liver injury. J Hepatol. 2019 Jun;70(6):1222–1261.
  • Garzel B, Zhang L, Huang SM, et al. A change in bile flow: looking beyond transporter inhibition in the development of drug-induced cholestasis. Curr Drug Metab. 2019;20(8):621–632.
  • van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692–706.
  • Raschi E, De Ponti F. Strategies for early prediction and timely recognition of drug-induced liver injury: the case of cyclin-dependent kinase 4/6 inhibitors. Front Pharmacol. 2019;10:1235.
  • Paech F, Bouitbir J, Hepatocellular Toxicity KS. Associated with tyrosine kinase inhibitors: mitochondrial damage and inhibition of glycolysis. Front Pharmacol. 2017 Jun;14(8):367.
  • Eno MR, El-Gendy Bel D, Cameron MD. P450 3A-catalyzed o-dealkylation of lapatinib induces mitochondrial stress and activates nrf2. Chem Res Toxicol. 2016 May 16;29(5):784–796.
  • Weng Z, Luo Y, Yang X, et al. Regorafenib impairs mitochondrial functions, activates AMP-activated protein kinase, induces autophagy, and causes rat hepatocyte necrosis. Toxicology. 2015 Jan;2(327):10–21.
  • Xue T, Luo P, Zhu H, et al. Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes. Toxicol Appl Pharmacol. 2012 Jun 15;261(3):280–291.
  • Zhang J, Salminen A, Yang X, et al. Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria. Arch Toxicol. 2017 Aug;91(8):2921–2938.
  • Guillouzo A, Corlu A, Aninat C, et al. The human hepatoma HepaRG cells: a highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem Biol Interact. 2007 May 20;168(1):66–73.
  • Kaur P, Robin, Metha RG, et al. Progression of conventional hepatic cell culture models to bioengineered HepG2 cells for evaluation of herbal bioactivities. Biotechnol Lett. 2018 Jun;40(6):881–893.
  • Dhalluin-Venier V, Besson C, Dimet S, et al. Imatinib mesylate-induced acute hepatitis with autoimmune features. Eur J Gastroenterol Hepatol. 2006 Nov;18(11):1235–1237.
  • Zitvogel L, Rusakiewicz S, Routy B, et al. Immunological off-target effects of imatinib. Nat Rev Clin Oncol. 2016 Jul;13(7):431–446.
  • Spigel DR, Reynolds C, Waterhouse D, et al. Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung cancer (checkmate 370). J Thorac Oncol. 2018 May;13(5):682–688.
  • Liu P, Zhao L, Pol J, et al. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat Commun. 2019 Apr 2;10(1):1486.
  • Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016 Jul 14;128(2):195–203.
  • Hirasawa M, Hagihara K, Okudaira N, et al. The possible mechanism of idiosyncratic lapatinib-induced liver injury in patients carrying human leukocyte antigen-DRB1*07:01. PLoS One. 2015 Jun 22;10(6):e0130928.
  • Xu CF, Johnson T, Wang X, et al. HLA-B*57:01 confers susceptibility to pazopanib-associated liver injury in patients with cancer. Clin Cancer Res. 2016 Mar 15;22(6):1371–1377.
  • Takimoto T, Kijima T, Otani Y, et al. Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity. Clin Lung Cancer. 2013 Sep;14(5):502–507.
  • Real M, Barnhill MS, Higley C, et al. Drug-induced liver injury: highlights of the recent literature. Drug Saf. 2019 Mar;42(3):365–387.
  • Shinozawa T, Kimura M, Cai Y, et al. High-fidelity drug-induced liver injury screen using human pluripotent stem cell-derived organoids. Gastroenterology. 2020 Oct ;8: S0016–5085(20)35228–8.
  • Bell CC, Lauschke VM, Vorrink SU, et al. Transcriptional, functional, and mechanistic comparisons of stem cell-derived hepatocytes, heparg cells, and three-dimensional human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury. Drug Metab Dispos. 2017 Apr;45(4):419–429.
  • Wang Z, Li W, Jing H, et al. Generation of hepatic spheroids using human hepatocyte-derived liver progenitor-like cells for hepatotoxicity screening. Theranostics. 2019;9(22):6690–6705.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.