Intratumoral concentrations of imatinib after oral administration in patients with glioblastoma multiforme.
Imatinib, an orally administered tyrosine kinase inhibitor of PDGF receptor, c-abl and c-kit, is currently in clinical trials to assess its efficacy in malignant gliomas. Although imatinib does not readily penetrate an intact blood-brain barrier (BBB), the extent to which it distributes into regions of high grade gliomas where the BBB is compromised has not been determined. Patients with recurrent high-grade gliomas for whom repeat surgical tumor debulking was clinically indicated received imatinib mesylate 600 mg orally once a day for seven days prior to surgery. Tissue samples were collected from different regions of the tumor and the approximate location of these samples was determined using frameless stereotactic neuronavigation. Plasma samples were obtained immediately before and after the resection. The concentration of imatinib in the plasma and tumor samples was determined using high performance liquid chromatography with mass spectrometric detection. Eleven tumor samples were obtained from three patients with recurrent glioblastoma multiforme. The median concentration of imatinib in these 11 tumor specimens was 1.34 microg/g (range 0.21-4.31 microg/g) and the median tumor-to-plasma ratio was 0.71 (range 0.28-3.03). These findings suggest that imatinib can reach intratumoral concentrations similar to those or higher than in plasma in regions of glioblastoma where the BBB is disrupted as indicated by contrast enhancement on magnetic resonance imaging.
Holdhoff
Matthias
M
Brain Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Cancer Research Building II, Suite 1 M-16 1550 Orleans Street, Baltimore, MD, 21231, USA. mholdho1@jhmi.edu
Supko
Jeffrey G
JG
Gallia
Gary L
GL
Hann
Christine L
CL
Bonekamp
David
D
Ye
Xiaobu
X
Cao
Bing
B
Olivi
Alessandro
A
Grossman
Stuart A
SA
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D013058:Mass Spectrometry; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate