A slow-release methotrexate formulation for intrathecal chemotherapy

Optimal anticancer treatment with cell cycle phase-specific antimetabolites requires a sustained maintenance of cytotoxic drug levels. However, drugs that can be administered intrathecally have short half-lives in cerebrospinal fluid (CSF) and require repeated administrations by lumbar punctures, which are painful and inconvenient. Implantable pumps are expensive and require surgery. In a rat model, a lipid-based formulation of methotrexate (Depo/methotrexate) was tested for extended maintenance of therapeutic CSF concentration after a single injection. The half-life of methotrexate in CSF after an intracisternal injection of Depo/methotrexate was 5.4 days compared to 0.30 days for unencapsulated methotrexate. This 18-fold increase in methotrexate half-life may make Depo/methotrexate useful for intrathecal chemotherapy of neoplastic meningitis.