title: Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation.
abstract: OBJECTIVE
  Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. We describe a Japanese woman with NSCLC and CNS metastases who was resistant to 75 mg daily erlotinib, but the metastases were improved by 150 mg daily erlotinib. We investigated the plasma and CSF concentrations of erlotinib at each dose as well as the correlation between the plasma and CSF concentrations of erlotinib.
  
  
  METHODS
  Including this patient, we administered 150 mg erlotinib daily to nine NSCLC patients with CNS metastases and measured the plasma and CSF concentrations just before administration on day 8. The concentrations were determined using high-performance liquid chromatography with ultraviolet detection.
  
  
  RESULTS
  The plasma and CSF concentrations of erlotinib at a dose of 75 mg were 433 and 14 nM, respectively. The plasma and CSF concentrations of erlotinib at a dose of 150 mg were increased to 1,117 and 44 nM, respectively. The mean ± standard deviation of CSF concentrations and penetration rates were 106 ± 59 nM and 4.5 ± 1.5%, respectively. There was a good correlation (R(2) = 0.84) between plasma and CSF concentrations (P = 0.0005).
  
  
  CONCLUSIONS
  This study indicates that CSF concentrations of erlotinib depend on its plasma concentration. As seen in this patient, high CSF concentrations of erlotinib can be achieved by high-dose administration, and this finding suggests the efficacy of high-dose administration, especially to refractory CNS metastases of NSCLC patients.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto, 606-8507, Japan. ytogashi@kuhp.kyoto-u.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Masago
authors.forename: Masahide
authors.initials: M
authors.lastname: Fukudo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsuchido
authors.forename: Chiyuki
authors.initials: C
authors.lastname: Okuda
authors.forename: Young Hak
authors.initials: YH
authors.lastname: Kim
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Ikemi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sakamori
authors.forename: Tadashi
authors.initials: T
authors.lastname: Mio
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Michiaki
authors.initials: M
authors.lastname: Mishima
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors