Intracerebral microdialysis for determination of the neuropharmacokinetics and neuropharmacodynamics of temozolomide in patients with primary or metastatic brain tumors

Abstract

2074 Background: Microdialysis (MD) is a technique for continuously analyzing concentrations of endogenous chemicals and drugs in the extracellular fluid (ECF) of a body tissue. The purpose of this study is to apply MD to the determination of the neuropharmacokinetics (nPK) and neuropharmacodynamics (nPD) of temozolomide (TMZ) following systemic administration. Methods: After surgical debulking, a MD catheter is placed in peritumoral brain tissue. Artificial cerebrospinal fluid (CSF) is continuously perfused at a rate of 1 μl/min. Fused CT/MRI scans confirm correct placement of the catheter in non-enhancing brain. Starting 24 hrs after surgery, patients are given a dose of TMZ (150 mg/m2), and serial ECF and plasma samples are collected over 24 hrs. TMZ concentrations are determined by LC/MS/MS. In vitro recovery of TMZ via the MD catheter has been determined to be 87±5.5% at a flow rate of 1 μl/min. Prior to and 24 hrs post TMZ, additional ECF samples are collected for analysis of glucose, glutamate, lactate, and pyruvate, which are measured using a CMA 600 Analyzer®. Results: Four patients have been enrolled. There have been no grade 3 or 4 catheter-related adverse events. Mean peak TMZ concentrations in brain ECF and plasma are 0.4±0.2 and 5.5±1.4 μg/ml, respectively. Mean TMZ AUC in brain ECF and plasma are 3.2±1.6 and 18.2±4.6 μg/mLxhr, with an average ECF/plasma AUC ratio of 18±4%. Mean basal levels of glucose, glutamate, lactate, and pyruvate in ECF are 0.4±0.3, 34±66, 3±4, 69±62 mM, respectively. No consistent changes were seen in these nPD markers 24 hrs after TMZ. Conclusions: Concentrations of TMZ in brain ECF obtained by MD are similar to published data of TMZ concentrations in the CSF (Clin Cancer Res 2004;10:3728–36). Baseline values of markers of brain tissue metabolism are consistent with previous data in patients with brain tumors (J Neuro-Oncol 2003; 61:151–60). Intracerebral MD is an important tool that can be applied to nPK/nPD studies of new and targeted agents for the treatment of brain tumors. (Supported by CA01727) No significant financial relationships to disclose.