Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing: a surrogate marker of brain penetration.
BACKGROUND
Vincristine (VCR) is used widely in oncology practice, and regular dosing is commonly associated with the development of sensorimotor or autonomic neuropathies. However, the incidence of VCR-related central nervous system (CNS) toxicity is comparatively low, suggesting that the blood-brain barrier may limit drug penetration into the brain parenchyma. This study determined whether measurable concentrations of VCR could be detected in the cerebrospinal fluid (CSF), as a surrogate marker of brain parenchyma penetration, after bolus intravenous injection in children without primary CNS pathology.


METHODS
The authors studied 17 pediatric patients ages 2.5-14.1 years (median, 6.8 years) with acute lymphoblastic leukemia or non-Hodgkin lymphoma without evidence of leptomeningeal disease. Patients received VCR 1.5 mg/m2 by intravenous bolus injection followed at varying intervals by lumbar puncture for scheduled intrathecal methotrexate administration under general anesthesia. Paired VCR concentrations in both plasma and CSF were measured in each patient simultaneously at times ranging from 8 minutes to 146 minutes after the VCR injection. Three patients were studied twice. The paired samples were stored at -40 degrees C until analysis using a high performance liquid chromatography assay with a sensitivity of 0.1 microg/L in CSF and 0.4 microg/L in plasma.


RESULTS
Plasma VCR concentrations ranged from 2.2 microg/L to 91.2 microg/L. No measurable VCR concentrations were detected in the CSF samples.


CONCLUSIONS
Measurable concentrations of VCR in CSF are not achieved after the administration of standard intravenous bolus doses of VCR. The current observations are consistent with the relative rarity of VCR-related CNS neurotoxicity compared with the commonly observed sensorimotor and autonomic neuropathies. These findings suggest that the penetration of VCR into the brain parenchyma of patients with a relatively intact blood-brain barrier is low and that VCR may have a limited role in the CNS-directed therapy of these patients.
Kellie
Stewart J
SJ
Oncology Unit and Department of Paediatrics and Child Health, the University of Sydney, The Children's Hospital at Westmead, Westmead, New South Wales, Australia. stewartk@chw.edu.au
Barbaric
Draga
D
Koopmans
Pauline
P
Earl
John
J
Carr
Deborah J
DJ
de Graaf
Siebold S N
SS
D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000134:cerebrospinal fluid*; D001812:Blood-Brain Barrier; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D014750:Vincristine / Q000008:administration & dosage / Q000134:cerebrospinal fluid*
D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine