Cerebrospinal Fluid Levels of Temozolomide as a Surrogate Marker for Brain Penetration.
Roger Stupp, Sandrine Ostermann, Serge Leyvraz, Chantal Csajka, Thierry Buclin, Laurent A Decosterd, University Hospital CHUV, Lausanne, Switzerland.

Presented at the American Society Of Clinical Oncology, 2001 Conference

Background: The poor clinical responses observed with many chemotherapy agents against brain tumors may be due to their restricted passage through the blood-brain barrier, resulting in insufficient levels at the tumor site. Cerebro-spinal fluid (CSF)-concentrations of a drug may give an estimation on its capacity to penetrate into the brain. Temozolomide (TMZ), a novel oral chemotherapy agent has been recently approved for malignant glioma. However, only little is known on drug penetration into the brain and CSF in humans.
Methods: TMZ concentrations were measured in CSF and plasma from patients enrolled in 2 clinical studies wherein patients with newly diagnosed or recurrent glioma were to receive either TMZ at a daily dose of 75mg/m2 and concomitant radiation [Stupp et al: PASCO 2000, abstract #632], or standard 200 mg/m2 daily x 5. A single CSF sample and 3 blood samples were taken at selected times between 1.5-6h after TMZ intake. Samples were immediately acidified for insuring TMZ stabilization and analyzed by high-performance liquid chromatography [Shen F et al: J Chromatog B 665:291, 1995]. Results: A total of 310 plasma and 58 CSF samples were collected from 33 patients, including 2 patients with multiple consecutive CSF-samples collected through an Ommaya-reservoir. Since TMZ has linear pharmacokinetics, all data were calculated after normalizing drug levels to a 200 mg/m2 dose. The TMZ CSF/plasma ratio progressively increases up to 40% until 4 hours after drug intake, time at which an equilibrium is reached.
Conclusions: These data indicate that TMZ readily crosses the blood-brain barrier. Population-based pharmacokinetic evaluation is ongoing. These values may allow future comparison with other potentially active agents for brain tumors. (supported in part by Schering-Plough Research Institute)
TMZ plasma & CSF concentrations

TMZ-dose (mg/m2)

n (samples)

Plasma (µg/ml)

CSF (µg/ml)

Mean ratio in %





24.8 ± 16.0





32.2 ±12.9




29.4 ±15.0

at equilibrium (after approx. 4 h)



39.7 ±11.4

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