The impact of bevacizumab on temozolomide concentrations in intracranial U87 gliomas.
OBJECTIVE
An important question in the sequencing of anti-cancer therapies in patients with glioblastoma (GBM) is whether concurrent anti-angiogenesis therapies improve or impair brain concentrations of concomitantly administered cytotoxic therapies. The purpose of this study is to assess the intratumoral disposition of temozolomide (TMZ) via microdialysis before and after bevacizumab in an intracranial GBM xenograft model.


METHODS
Microdialysis probes were placed within tumor and contralateral brain in athymic rats bearing U87 intracerebral gliomas. TMZ (50 mg/kg oral) was administered 10 days thereafter. Extracellular fluid (ECF) was collected for 6 h. BEV was administered (10 mg/kg IV), and TMZ was re-dosed (50 mg/kg oral) 36 h thereafter with additional ECF collection. All ECF samples were assessed for TMZ concentration with liquid chromatography-tandem mass spectrometry.


RESULTS
Tumor TMZ mean area under the concentration-time curve (AUC(0-∞)) was 3.35 μg h/mL pre-BEV. Post-BEV, tumor mean TMZ AUC(0-∞) was 3.98 μg h/mL. In non-tumor brain, mean TMZ AUC(0-∞) pre-BEV was 3.22 μg h/mL and post-BEV was 3.34 μg h/mL.


CONCLUSIONS
There were no statistically significant changes in TMZ pharmacokinetics before or after BEV in the athymic rat U87 intracranial glioma model. BEV and TMZ are being investigated as a combination therapy in several ongoing studies for patients with glioma. These data reassuringly suggest that BEV does not significantly change the ECF tumor concentrations of TMZ in either tumor-bearing or normal brain when dosed 36 h prior to TMZ.
Department of Neurosurgery, Tel-Aviv Medical Center, Tel Aviv, Israel.
Rachel
R
Grossman
Michelle A
MA
Rudek
Harry
H
Brastianos
Patti
P
Zadnik
Henry
H
Brem
Betty
B
Tyler
Jaishri O
JO
Blakeley
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004347:Drug Interactions; D045604:Extracellular Fluid / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis / Q000379:methods; D051381:Rats; D011923:Rats, Nude; D000077204:Temozolomide; D013997:Time Factors
D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003606:Dacarbazine; D000077204:Temozolomide