DDEL-01. ANIMAL STUDIES WITH A NEW CNS DRUG DELIVERY DEVICE TO EFFECTIVELY TREAT LEPTOMENINGEAL CARCINOMATOSIS PATIENTS

Abstract

Abstract Background Appropriate drug distribution is needed for effective treatment of brain metastases and leptomeningeal carcinomatosis. 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 active 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 sheep and non-human primates. METHODS The EnClear device utilizes two implantable catheters (intracranial in the ventricular system and lumbar thecal sac) and an extracorporeal pump that controls the speed and direction of CSF flow. Software monitors the output from sensor arrays for pressure, respiration, and heart rate. Gadolinium and MRI were used to determine the CSF flow characteristics. Administration of Methotrexate via the EnClear system was compared to current two standards of delivery, intracerebroventricular or lumbar intrathecal administration. Methotrexate levels were measured with Liquid Chromatography/Mass Spectrometry 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 the 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, the EnClear device has for the first time, demonstrated increased brain parenchymal drug levels via intrathecal delivery. In addition to the drug parenchyma, drug delivery with this novel device has shown improved distribution throughout CNS and leptomeninges as compared to traditional intrathecal drug delivery and decreased peripheral distribution.