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

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.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 plasma3 CSF ), 7.2 ؋ 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 plasma3 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.

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

“…Similar results were seen in a primary GBM sample treated with or without 50 mM of TMZ (Supplementary Figure S3). Within specific subpopulations, the analyzed cells also presented a significant increase in other GSC markers, such as Sox2, Oct4, and Nestin (11,12, and 25% on average, respectively; ***Po0.001, Figure 1a and Supplementary Figure S2A). Additionally, they co-expressed markers of pluripotency and stemness -14% of GSCs co-expressed SOX2, 9% co-expressed Oct4, and 10% co-expressed Nestin (***Po0.001, Figure 1b and Supplementary Figure S2B).…”

“…The clinically relevant regimen for TMZ consists of 150-200 mg/m 2 /day, via oral administration, on days 1-5 of a 28-day cycle. 1 However, its peak concentration measured is only 50 mmol/l in patient's blood samples [9][10][11][12] and 5 mmol/l in the CSF. 12 Thus, it has been proposed that the intratumoral concentration may not exceed 50 mmol/l.…”

“…1 However, its peak concentration measured is only 50 mmol/l in patient's blood samples [9][10][11][12] and 5 mmol/l in the CSF. 12 Thus, it has been proposed that the intratumoral concentration may not exceed 50 mmol/l. 9 On the basis of this, we chose to use 5 and 50 mmol/l of TMZ throughout our experiments.…”

MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis

“…shown that all CD133-positive glioblastoma cells tested are resistant to temozolomide-induced cell death at the maximum concentrations reached in the spinal fluid and in the plasma (21). In this study, CD133-positive glioblastoma cells were treated for 2, 4 and 6 days with increasing doses of TMZ.…”

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

“…1A). When these cells were subjected to cell death assay after treatment with clinically relevant concentrations ($50 lM) of temozolomide [18], we found that cell death was induced in close (inverse) In (E), the graph shows the percentage of dead cells (means þ standard deviations of three independent experiments). *, p < .01, **, p < .05, n.s., not significant.…”