The effect of increasing topotecan infusion from 30 minutes to 4 hours on the duration of exposure in cerebrospinal fluid.
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.


METHODS
We evaluated this approach in a 51-year-old woman with breast cancer metastatic to the CNS. TPT was administered at 1.5 mg/m2/day (cycle 1) and 1.0 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 1.8- and 1.7-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.
Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh, Cancer Institute, Pennsylvania 15213, USA. zamboniwc@msx.upmc.edu
W C
WC
Zamboni
D I
DI
Lüftner
M J
MJ
Egorin
M
M
Schweigert
O
O
Sezer
T
T
Richter
J J
JJ
Natale
K
K
Possinger
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D019772:Topotecan / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019772:Topotecan