Abstract BACKGROUND Appropriate drug distribution is needed for effective treatment of brain metastases and leptomeningeal disease. Lack of proper drug bioavailability in the CNS contributes to the poor outcome in these patients. EnClear Therapies has developed a device delivering intrathecal therapeutics utilizing the dynamic control of CSF flow through an external pump. Herein, we look at intrathecal drug delivery of methotrexate with EnClear’s system and its impact of drug concentration in CNS tissue in sheep and non-human primates. METHODS EnClear’s system utilizes two implantable catheters (lateral ventricle and lumbar thecal sac) and an extracorporeal pump that controls the speed and direction of CSF flow. Software continuously monitors and reports the output from sensor arrays for pressure, respiration, and heart rate. Imaging studies were used to track the CSF flow characteristics during the use of EnClear’s system. Data from administration of methotrexate followed by the use of EnClear’s system was compared to the current standard of delivery, intracerebroventricular or lumbar intrathecal administration. Methotrexate levels were measured with LC/MS in CSF, blood, and multiple CNS and peripheral tissues. RESULTS There was a two-fold increase in methotrexate levels in multiple regions of the brain including deeper brain structures including the striatum using EnClear's system, compared to traditional lumbar intrathecal and intracerebroventricular delivery. Higher peak levels of methotrexate were reached in the CSF with the use of EnClear’s system, with simultaneous reduction in the peripheral nerves and systemic tissues – a potential source of toxicity. CONCLUSIONS In large animal studies, EnClear’s system has for the first time, demonstrated increased brain parenchymal drug levels via intrathecal delivery. Drug delivery with this novel device has shown improved distribution throughout the CNS and leptomeninges as compared to traditional intrathecal drug delivery and decreased peripheral distribution.