Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment.
Most lymphomas that involve the central nervous system are B-cell neoplasms that express the cell surface molecule CD20. After intravenous administration, rituximab can be reproducibly measured in the cerebrospinal fluid (CSF) in patients with primary central nervous system lymphoma; however, the CSF levels of rituximab are approximately 0.1% of serum levels associated with therapeutic activity in patients with systemic non-Hodgkin lymphoma. Because lymphomatous meningitis is a frequent complication of non-Hodgkin lymphoma, we have conducted an analysis of the safety and pharmacokinetics of direct intrathecal administration of rituximab using cynomolgus monkeys. No significant acute or delayed toxicity, neurologic or otherwise, was detected. Pharmacokinetic analysis suggests that drug clearance from the CSF is biphasic, with a terminal half-life of 4.96 hours. A phase 1 study to investigate the safety and pharmacokinetics of intrathecal rituximab in patients with recurrent lymphomatous meningitis will be implemented based on these findings.
Rubenstein
James L
JL
Division of Hematology/Oncology, Comprehensive Cancer Center, Cancer Research Institute, Department of Neurosurgery, UCSF, San Francisco, CA 94143, USA. jamesr@medicine.ucsf.edu
Combs
Dan
D
Rosenberg
Jay
J
Levy
Arthur
A
McDermott
Michael
M
Damon
Lloyd
L
Ignoffo
Robert
R
Aldape
Kenneth
K
Shen
Arthur
A
Lee
Dana
D
Grillo-Lopez
Antonio
A
Shuman
Marc A
MA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D058846:Antibodies, Monoclonal, Murine-Derived; D019540:Area Under Curve; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006207:Half-Life; D007278:Injections, Spinal; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab