Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer

• Published in: Cancer chemotherapy and pharmacology Vol. 70; no. 3; pp. 399 - 405
• Main Authors: Togashi, Yosuke, Masago, Katsuhiro, Masuda, Satohiro, Mizuno, Tomoyuki, Fukudo, Masahide, Ikemi, Yasuaki, Sakamori, Yuichi, Nagai, Hiroki, Kim, Young Hak, Katsura, Toshiya, Mishima, Michiaki
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.09.2012; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - blood; Antineoplastic Combined Chemotherapy Protocols - cerebrospinal fluid; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Asian Continental Ancestry Group; Biological and medical sciences; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Central nervous system; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - secondary; Chromatography, High Pressure Liquid; Erlotinib Hydrochloride; Female; Humans; Japan; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medical sciences; Medicine; Medicine & Public Health; Meningeal Neoplasms - drug therapy; Meningeal Neoplasms - secondary; Middle Aged; Mutation; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pneumology; Quinazolines - administration & dosage; Receptor, Epidermal Growth Factor - genetics; Tandem Mass Spectrometry; Treatment Outcome; Tumors of the respiratory system and mediastinum; Japan; Epidermal growth factor receptor gene mutation; Cerebrospinal fluid; Erlotinib; Gefitinib; Leptomeningeal metastases; Non-small cell lung cancer; Antineoplastic agent; Quinazoline derivatives; Lung cancer; Metastasis; non-small cell lung carcinoma; EGFR tyrosine kinase inhibitor; Epidermal growth factor receptor; Gene; Bronchus disease; Genetics; Protein-tyrosine kinase; Human; Lung disease; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Transferases; Enzyme inhibitor; Patient; Malignant tumor; Concentration; Growth factor receptor; Mutation; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-1929-4

Purpose 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.