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Therapeutic Effects and Adverse Drug Reactions are Affected by Icotinib Exposure and CYP2C19 and EGFR Genotypes in Chinese Non-Small Cell Lung Cancer Patients

  • Chen, Jia (Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences) ;
  • Zheng, Xin (Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences) ;
  • Liu, Dong-Yang (Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences) ;
  • Zhao, Qian (Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences) ;
  • Wu, Yi-Wen (Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences) ;
  • Tan, Fen-Lai (Zhejiang Beta Pharma, Inc.) ;
  • Wang, Yin-Xiang (Zhejiang Beta Pharma, Inc.) ;
  • Jiang, Ji (Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences) ;
  • Hu, Pei (Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences)
  • Published : 2014.09.15

Abstract

Background: The aim of this study was to evaluate how CYP2C19 affects icotinib and metabolite' exposure, and to determine whether the exposure and EGFR genotype influences survival time, tumor metastasis and adverse drug reactions. Materials and Methods: 274 NSCLC patients who accepted 125mg icotinib/t.i.d. were chosen from a phase III study. Blood samples were obtained in $672^{nd}$ ($4^{th}$ week) and $1,680^{th}$ hours ($10^{th}$ week), and plasma was used to quantify the concentration of icotinib and blood cells were sampled to check the genotypes. Clinical data were also collected at the same time, including EGFR genotypes. Plasma concentrations were assessed by HPLC-MS/MS and genotype by sequencing. All data were analyzed through SPSS 17.0 and SAS 9.2. Results: CYP 2C19 genotypes affected bio-transformation from icotinib to M24 and M26, especially in poor-metabolisers. Higher icotinib concentrations (>1000 ng/mL) not only increased patient PFS and OS but also reduced tumor metastasis. Patients with mutant EGFR experienced a higher median PFS and OS (234 and 627 days), especially those with the 19del genotype demonstrating higher PR ratio. Patients who suffered grade II skin toxicity had a higher icotinib exposure than those with grade I skin toxicity or no adverse effects. Liver toxic reactions might occur in patients with greater M20 and M23 plasma concentrations. Conclusions: CYP2C19 polymorphisms significantly affect icotinib, M24 and M26 exposure. Patients with mutant EGFR genotype and higher icotinib concentration might have increased PFS and OS and lower tumor metastasis. Liver ADR events and serious skin effects might be respectively induced by greater M20, M23 and icotinib concentrations.

Keywords

Icotinib;metabolites;CYP2C19;EGFR;PFS and OS;liver ADR

References

  1. Alimujiang S, Zhang T, Han ZG, et al. (2013) Epidermal growth factor receptor tyrosine kinase inhibitor versus placebo as maintenance therapy for advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Asian Pac J Cancer Prev, 14, 2413-9. https://doi.org/10.7314/APJCP.2013.14.4.2413
  2. Camidge DR. (2013) Icotinib: kick-starting the Chinese anticancer drug industry. Lancet Oncol, 14, 913-4. https://doi.org/10.1016/S1470-2045(13)70385-1
  3. Gao Z, Chen W, Zhang X, et al. (2013) Icotinib, a potent and specific EGFR tyrosine kinase inhibitor, inhibits growth of squamous cell carcinoma cell line A431 through negatively regulating AKT signaling. Biomed Pharmacother, 67, 351-6. https://doi.org/10.1016/j.biopha.2013.03.012
  4. Hirsch FR, Varella-Garcia M, Bunn PA, et al. (2006) Molecular predictors of outcome with gefitinib in a phase III placebocontrolled study in advanced non-small-cell lung cancer. J Clin Oncol, 24, 5034-42. https://doi.org/10.1200/JCO.2006.06.3958
  5. Liam CK, Leow HR, How SH, et al. (2014) Epidermal growth factor receptor mutations in non- small cell lung cancers in a multiethnic Malaysian patient population. Asian Pac J Cancer Prev, 15, 321-6. https://doi.org/10.7314/APJCP.2014.15.1.321
  6. Liu D, Jiang J, Zhang L, et al. (2011) Metabolite characterization of a novel anti-cancer agent, icotinib, in humans through liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Rapid Commun Mass Spectrom, 25, 2131-40. https://doi.org/10.1002/rcm.5061
  7. Liu D, Jiang J, Zhang L, et al. (2014) Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects. Cancer Chemother Pharmacol, (in press).
  8. Mu X, Zhang Y, Qu X, et al. (2013) Ubiquitin ligase Cbl-b is involved in icotinib (BPI-2009H)-induced apoptosis and G1 phase arrest of EGFR mutation-positive non-small-cell lung cancer. Biomed Res Int, 2013, 726375.
  9. Pan JB, Hou YH, Zhang GJ. (2013) Correlation between EGFR mutations and serum tumor markers in lung adenocarcinoma patients. Asian Pac J Cancer Prev, 14, 695-700. https://doi.org/10.7314/APJCP.2013.14.2.695
  10. Qi WX, Shen Z, Lin F, et al. (2012) Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: a systematic review and meta-analysis. Asian Pac J Cancer Prev, 13, 5177-82. https://doi.org/10.7314/APJCP.2012.13.10.5177
  11. Ruan CJ, Liu DY, Jiang J, et al. (2012) Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers. Eur J Clin Pharmacol, 68, 1677-80. https://doi.org/10.1007/s00228-012-1288-4
  12. Shao L, Zhang B, He C, et al. (2014) Efficacy and safety of icotinib in Chinese patients with advanced non-small cell lung cancer after failure of chemotherapy. Chin Med J, 127, 266-71.
  13. Shi Y, Zhang L, Liu X, et al. (2013) Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 noninferiority trial. Lancet Oncol, 14, 953-61. https://doi.org/10.1016/S1470-2045(13)70355-3
  14. Song Z, Yu X, Cai J, et al. (2013) [Efficacy of icotinib for advanced non-small cell lung cancer patients with EGFR status identified]. Zhongguo Fei Ai Za Zhi, 16, 138-43.
  15. Takano T, Fukui T, Ohe Y, et al. (2008) EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J Clin Oncol, 26, 5589-95. https://doi.org/10.1200/JCO.2008.16.7254
  16. Tan F, Shen X, Wang D, et al. (2012) Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies. Lung Cancer, 76, 177-82. https://doi.org/10.1016/j.lungcan.2011.10.023
  17. Usuda K, Sagawa M, Motono N, et al. (2014) Relationships between EGFR mutation status of lung cancer and preoperative factors - are they predictive? Asian Pac J Cancer Prev, 15, 657-62. https://doi.org/10.7314/APJCP.2014.15.2.657
  18. Wang HP, Zhang L, Wang YX, et al. (2011) Phase I trial of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in Chinese patients with non-small cell lung cancer. Chin Med J, 124, 1933.
  19. Zhao Q, Shentu J, Xu N, et al. (2011) Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung Cancer, 73, 195-202. https://doi.org/10.1016/j.lungcan.2010.11.007

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