The impact of bevacizumab on temozolomide concentrations in intracranial U87 gliomas

Purpose: 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.