Annals of Oncology 12:119-122, 2001
© 2001 European Society for Medical Oncology
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The effect of increasing topotecan infusion from 30 minutes to 4 hours on the duration of exposure in cerebrospinal fluid
1Program of Molecular Therapeutics and Drug Discovery, University of Putsburgh, Cancer Institute Pennsylvania, USA
2Department of Pharmaceutical Sciences School of Pharmacy, University of Pittsburgh Pennsylvania, USA
3Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Puttsburgh Pennsylvania, USA
4Medizinische Klinik and Poliklinik II, Schwerpunkt Onkologie and Hâmatologie, Universuãtsklmikum Charité, Campus Hitte, Humboldt-Universität Berlin, Germany
5Department of Pharmacology, School of Medicine, University of Pittsburgh,Pittsburgh Pennsylvania, USA
W C Zamborn, PharmD University of Pittsburgh Cancer Institute Biomedical Science Tower, E-1040 200 Lothrop Street Pittsburgh, PA 15213 USA E-mail zamboniwc{at}max.upmc.edu
BACKGROUND: The development of metastatic disease throughout the neuroaxis from primary central nervous system (CNS) tumors and non-CNS tumors suggests the cerebrospinal fluid (CSF) is an important source of exposure for chemotherapeutic agents. In non-human primates, a 4-hour, as compared to a 30-minute, topotecan (TPT) infusion prolonged TPT exposure in the CSF
PATIENT AND METHODS: We evaluated this approach in a 51-year-old woman with breast cancer metastatic to the CNS TPT was administered at 15 mg/m2/day (cycle 1) and 10 mg/m2/day (cycles 2 and 3) as a 30-minute infusion on days 0–4, and as a 4-hour infusion on day 5 Cycles were repeated every 21 days Plasma, lateral ventricular CSF, and lumbar CSF samples were obtained after 30-minute and 4-hour infusions, and assayed for TPT lactone and total by HPLC A three-compartment model was used to calculate area under the plasma (AUCplasma) and lateral ventricular CSF (AUCCSF) concentation-time curves. TPT CSF penetration was calculated as the ratio of AUCCSF to AUCplasma
RESULTS: Mean ± SD values for TPT total CSF penetration in lateral CSF after 30-minute and 4-hour infusions were 0 25 ± 0 15 and 0 29 ± 0 02. respectively. TPT total lumbar CSF concentration was 3-fold greater after a 4-hour as compared to a 30-minute infusion For TPT lactone and TPT total, time > 1 ng/ml in lateral CSF was 18- and 17-fold greater, respectively, for a 4-hour as compared to a 30-minute infusion
CONCLUSIONS: Prolonging TPT infusion from 30 minute to 4 hours increases the duration of exposure in the CSF This study demonstrates the ability to develop treatment strategies of systemically administered chemotherapy to enhance cytotoxic exposure in the CSF
cerebrospinal fluid (CSF),, pharmacokinelics,, topotecan
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