Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.
OBJECTIVE
Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them.


METHODS
We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry.


RESULTS
The concentration and penetration rate of gefitinib (mean ± standard deviation) in the CSF were 3.7 ± 1.9 ng/mL (8.2 ± 4.3 nM) and 1.13 ± 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 ± 16.8 ng/mL (66.9 ± 39.0 nM) and 2.77 ± 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P = 0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib.


CONCLUSIONS
This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Japan. ytogashi@kuhp.kyoto-u.ac.jp
Yosuke
Y
Togashi
Katsuhiro
K
Masago
Satohiro
S
Masuda
Tomoyuki
T
Mizuno
Masahide
M
Fukudo
Yasuaki
Y
Ikemi
Yuichi
Y
Sakamori
Hiroki
H
Nagai
Young Hak
YH
Kim
Toshiya
T
Katsura
Michiaki
M
Mishima
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D044466:Asian People; 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; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib