Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients

• DOI: 10.1158/1078-0432.ccr-03-0807
• Publication Date: 2005-09-21T23:56:19Z
• Authors: Sandrine Ostermann; Chantal Csajka; Thierry Buclin; Serge Leyvraz; Ferdy Lejeune; Laurent A. Decosterd; Roger Stupp
• Keywords: Temozolomide; Concomitant; Brain tumor; Elimination rate constant

Abstract Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent mainly used for treatment malignant tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, characterize covariates explore relationships between systemic or cerebral drug exposure clinical outcomes. Experimental Design: levels were measured by high-performance liquid chromatography CSF samples from 35 patients newly diagnosed recurrent gliomas. population pharmacokinetic analysis performed nonlinear mixed-effect modeling software. Drug exposure, defined area under concentration-time curve (AUC) CSF, estimated each patient correlated toxicity, survival, progression-free survival. Results: A three-compartment model first-order absorption transfer rates described data appropriately. Oral clearance 10 liter/h; volume distribution (VD), 30.3 liters; constant rate, 5.8 h−1; elimination half-time, 2.1 h; rate (Kplasma→CSF), 7.2 × 10−4h−1 backwards 0.76 h−1. Body surface significantly influenced both VD, sex dependent. AUCCSF corresponded 20% AUCplasma. trend toward an increased Kplasma→CSF 15% observed case concomitant radiochemotherapy. No significant correlations AUC survival apparent after deduction dose-effect. Conclusions: This first human study quantify penetration. AUCCSF/AUCplasma ratio 20%. Systemic exposures are not better predictors than cumulative dose alone efficacy safety.