Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients.
Clin Cancer Res
; 10(11): 3728-36, 2004 Jun 01.
Article
en En
| MEDLINE
| ID: mdl-15173079
ABSTRACT
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. EXPERIMENTALDESIGN:
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.
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Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Encefálicas
/
Dacarbazina
/
Glioma
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2004
Tipo del documento:
Article
País de afiliación:
Suiza