Universität zu Köln

Buesker, Soeren, Jaeger, Walter, Poschner, Stefan, Mayr, Lisa, Al Jalali, Valentin, Gojo, Johannes, Azizi, Amedeo A., Ullah, Sami ORCID: 0000-0003-1891-4524, Bilal, Muhammad, El Tabei, Lobna, Fuhr, Uwe ORCID: 0000-0001-7087-5871 and Peyrl, Andreas (2022). Pharmacokinetics of metronomic temozolomide in cerebrospinal fluid of children with malignant central nervous system tumors. Cancer Chemother. Pharmacol., 89 (5). S. 617 - 628. NEW YORK: SPRINGER. ISSN 1432-0843

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Abstract

Purpose Although temozolomide is widely used in the treatment of childhood central nervous system (CNS) tumors, information on its pharmacokinetic profile in the brain or cerebrospinal fluid (CSF) is sparse. This study aimed at investigating whether measurable and clinically relevant concentrations of temozolomide are reached and maintained in CSF for continuous oral administration in pediatric patients. A population pharmacokinetic model was developed to quantify CSF penetration of temozolomide. Methods Eleven pediatric CNS tumor patients (aged 4-14 years) treated with oral temozolomide using a metronomic schedule (24-77 mg/m(2)/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). Results Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24-5.99) mu g/ml and 0.37 (0.06-1.76) mu g/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 (V-c) 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 (AUC(CSF) / AUC(plasma) ratio) of 37%. Conclusion Metronomic oral temozolomide penetrates into the CSF in pediatric patients, with even higher concentration levels compared to adults.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Buesker, Soeren UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaeger, Walter UNSPECIFIED UNSPECIFIED UNSPECIFIED Poschner, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayr, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Al Jalali, Valentin UNSPECIFIED UNSPECIFIED UNSPECIFIED Gojo, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Azizi, Amedeo A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ullah, Sami UNSPECIFIED orcid.org/0000-0003-1891-4524 UNSPECIFIED Bilal, Muhammad UNSPECIFIED UNSPECIFIED UNSPECIFIED El Tabei, Lobna UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED orcid.org/0000-0001-7087-5871 UNSPECIFIED Peyrl, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-678659
DOI:	10.1007/s00280-022-04424-4
Journal or Publication Title:	Cancer Chemother. Pharmacol.
Volume:	89
Number:	5
Page Range:	S. 617 - 628
Date:	2022
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-0843
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIGH-GRADE GLIOMA; PHASE-I TRIAL; POPULATION PHARMACOKINETICS; JOINT ITCC; RECURRENT; RADIOTHERAPY; COMBINATION; IRINOTECAN; PLASMA; TEMIRI Multiple languages Oncology; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67865