In a recent paper entitled Pharmacokinetics of metronomic temozolomide in cerebrospinal fluid of children with malignant central nervous system tumors and published in Cancer Chemotherapy Pharmacology, Sören Büsker, Walter Jäger, Stefan Poschner, Lisa Mayr , Valentin Al Jalali, Johannes Gojo, Amedeo A Azizi, Sami Ullah, Muhammad Bilal, Lobna El Tabei, Uwe Fuhr, Andreas Peyrlfrom the Center for Pharmacology, Faculty of Medicine, University Hospital Cologne, University of Cologne, the Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, the Department of Pediatric and Adolescent Medicine, Comprehensive Center for Pediatrics, the Department of Clinical Pharmacolog, the Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany. report about temozolomide concentrations in plasma samples from children receiving metronomic temozolomide. Indeed, aAlthough temozolomide is widely used in the treatment of childhood central nervous system tumors, data on its PK profile in the brain or cerebrospinal fluid (CSF) remains sparse.

Eleven pediatric CNS tumor patients (aged 4-14 years) who were treated with oral metronomic temozolomide (24-77 mg/m2/day) were included. Temozolomide concentrations in 28 plasma samples and 64 CSF samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modeling and simulations were performed using non-linear mixed effects modeling (NONMEM 7.4.2). Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24-5.99) µg/ml and 0.37 (0.06-1.76) µg/ml, respectively. A two-compartment model (central/plasma [1], CSF [2]) with first-order absorption, first-order elimination, and a transit compartment between CSF and plasma adequately described the data. Population mean estimates for clearance (CL) and the volume of distribution in the central compartment (Vc) were 3.29 L/h (95% confidence interval (CI) 2.58-3.95) and 10.5 L (8.17-14.32), respectively. Based on simulations, we found a median area under the concentration vs. time curve ratio (AUCCSF / AUCplasma ratio) of 37%.

The authors conclude that metronomic oral temozolomide penetrates well into the CSF in pediatric patients, with even higher concentration levels compared to adults.

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