Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients

Détails

ID Serval
serval:BIB_3B2D8C83B78B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients
Périodique
Clinical Cancer Research
Auteur(s)
Ostermann  S., Csajka  C., Buclin  T., Leyvraz  S., Lejeune  F., Decosterd  L. A., Stupp  R.
ISSN
1078-0432 (Print)
Statut éditorial
Publié
Date de publication
06/2004
Volume
10
Numéro
11
Pages
3728-36
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jun 1
Résumé
PURPOSE: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes. EXPERIMENTAL DESIGN: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. RESULTS: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (V(D)), 30.3 liters; absorption constant rate, 5.8 h(-1); elimination half-time, 2.1 h; transfer rate from plasma to CSF (K(plasma-->CSF)), 7.2 x 10(-4)h(-1) and the backwards rate, 0.76 h(-1). Body surface area significantly influenced both clearance and V(D), and clearance was sex dependent. The AUC(CSF) corresponded to 20% of the AUC(plasma). A trend toward an increased K(plasma-->CSF) of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. CONCLUSIONS: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC(CSF)/AUC(plasma) ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.
Mots-clé
Adult Aged Antineoplastic Agents, Alkylating/blood/cerebrospinal fluid Area Under Curve Brain Neoplasms/blood/cerebrospinal fluid/*drug therapy Chromatography, High Pressure Liquid Clinical Trials Dacarbazine/*analogs & derivatives/*blood/*cerebrospinal fluid Disease-Free Survival Female Glioma/blood/cerebrospinal fluid/*drug therapy Humans Kinetics Male Middle Aged Treatment Outcome
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/01/2008 8:39
Dernière modification de la notice
20/08/2019 13:31
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