Cancer Res Treat.  2020 Jan;52(1):181-188. 10.4143/crt.2019.131.

Factors Influencing Imatinib-Induced Hepatotoxicity

Affiliations
  • 1College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
  • 2Department of Pharmacy, Seoul National University Hospital, Seoul, Korea

Abstract

Purpose
Although imatinib-induced hepatotoxicity may aggravate the patient’s clinical condition and alter the treatment plan, the underlying mechanism of and factors influencing imatinibinduced hepatotoxicity have rarely been investigated. The purpose of this study was to investigate factors affecting on the incidence of hepatotoxicity within 90 days after starting imatinib treatment and time to onset of imatinib-induced hepatotoxicity.
Materials and Methods
We retrospectively evaluated the records of 177 patients receiving imatinib from October 2012 to September 2017. The analyzed factors included sex, age, body weight, body surface area, underlying disease, and concomitant drugs.
Results
The proportion of patients with hepatotoxicity within 90 days after imatinib administration was 33.9%. Proton pump inhibitors (PPIs) increased the incidence of hepatotoxicity approximately 3.8-fold and doubled the hazard of time to reach hepatotoxicity. Patients with liver disease or hepatitis B virus (HBV) carriers had a more than 8-fold higher risk of hepatotoxicity and a 5.2-fold increased hazard of hepatotoxicity compared to those without liver disease or HBV. Patients with body weight under 55 kg had a 2.2-fold higher risk for occurrence of hepatotoxicity. Patients with an imatinib dose > 400 mg had a 2.3-fold increased hazard of time to reach hepatotoxicity compared to those with an imatinib dose ≤ 400 mg.
Conclusion
The findings of this study suggest that the use of PPIs and presence of liver disease or HBV were associated with imatinib-induced hepatotoxicity. Thus, close liver function monitoring is recommended, especially in patients with liver impairment or using PPIs.

Keyword

Imatinib mesylate; Chemical and drug induced liver injury; Time to reach hepatotoxicity; Proton pump inhibitors; Liver diseases; Hepatitis B virus

Figure

  • Fig. 1. Area under the receiver operating characteristic curve for factors affecting imatinib-induced hepatotoxicity. (A) Model I included for analysis the body surface area, presence of liver disease or hepatitis B virus infection, and proton pump inhibitors. (B) Model II included for analysis the body weight, presence of liver disease or hepatitis B virus infection, and proton pump inhibitors.


Reference

References

1. Zhuang W, Xie JD, Zhou S, Zhou ZW, Zhou Y, Sun XW, et al. Can therapeutic drug monitoring increase the safety of Imatinib in GIST patients? Cancer Med. 2018; 7:317–24.
Article
2. Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002; 8:935–42.
3. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005; 44:879–94.
Article
4. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348:994–1004.
5. Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour:a randomised, double-blind, placebo-controlled trial. Lancet. 2009; 373:1097–104.
6. Johnson JR, Bross P, Cohen M, Rothmann M, Chen G, Zajicek A, et al. Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Clin Cancer Res. 2003; 9:1972–9.
7. Mindikoglu AL, Regev A, Bejarano PA, Martinez EJ, Jeffers LJ, Schiff ER. Imatinib mesylate (gleevec) hepatotoxicity. Dig Dis Sci. 2007; 52:598–601.
Article
8. Kong JH, Yoo SH, Lee KE, Nam SH, Kwon JM, Lee SM, et al. Early imatinib-mesylate-induced hepatotoxicity in chronic myelogenous leukaemia. Acta Haematol. 2007; 118:205–8.
9. Takikawa H. Recent status of drug-induced liver injury and its problem in japan. Jpn Med Assoc J. 2010; 53:243–7.
10. Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist. 2004; 9:271–81.
Article
11. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013; 36:491–503.
Article
12. Highlights of prescribing information: Gleevec (imatinib mesylate) [Internet]. East Hanover, NJ: Novartis Pharmaceuticals Corporation;2018. [cited 2018 Nov 5]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021588s053lbl.pdf.
13. Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008; 26:626–32.
Article
14. Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008; 111:4022–8.
Article
15. Eadie LN, Hughes TP, White DL. Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib. Clin Pharmacol Ther. 2014; 95:294–306.
Article
16. Burger H, Nooter K. Pharmacokinetic resistance to imatinib mesylate: role of the ABC drug pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the oral bioavailability of imatinib. Cell Cycle. 2004; 3:1502–5.
Article
17. Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008; 9:105–27.
Article
18. Cho S, Yee J, Kim JY, Jeong Rhie S, Gwak HS. Effects of concomitant medication use on gefitinib-induced hepatotoxicity. J Clin Pharmacol. 2018; 58:263–8.
Article
19. Lodato F, Azzaroli F, Di Girolamo M, Feletti V, Cecinato P, Lisotti A, et al. Proton pump inhibitors in cirrhosis: tradition or evidence based practice? World J Gastroenterol. 2008; 14:2980–5.
Article
20. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2011; 21:152–61.
21. Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE. hOCT 1 and resistance to imatinib. Blood. 2005; 106:1133–4.
Article
22. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004; 104:3739–45.
Article
23. Bourdet DL, Pritchard JB, Thakker DR. Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005; 315:1288–97.
Article
24. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011; 117:e75–87.
Article
25. White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood. 2006; 108:697–704.
Article
26. Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther. 2012; 92:203–13.
Article
27. Deininger MW, Druker BJ. Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev. 2003; 55:401–23.
Article
28. Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, et al. Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol. 2004; 54:290–4.
Article
29. Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U, et al. Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol. 2004; 53:102–6.
Article
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