title: Therapeutic effects and adverse drug reactions are affected by icotinib exposure and CYP2C19 and EGFR genotypes in Chinese non-small cell lung cancer patients.
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.
  
  
  METHODS
  274 NSCLC patients who accepted 125 mg icotinib/t.i.d. were chosen from a phase III study. Blood samples were obtained in 672 nd (4th week) and 1,680 th hours (10th 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.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China E-mail : pei.hu.pumc@gmail.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.forename: Dong-Yang
authors.initials: DY
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Wu
authors.forename: Fen-Lai
authors.initials: FL
authors.lastname: Tan
authors.forename: Yin-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics; D002681:China; D002851:Chromatography, High Pressure Liquid; D043844:Crown Ethers / Q000378:metabolism / Q000627:therapeutic use*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D003875:Drug Eruptions / Q000209:etiology / Q000235:genetics; D005260:Female; D018773:Genes, erbB-1 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011799:Quinazolines / Q000378:metabolism / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19