Application and Safety of Externally Controlled Metronomic Drug Delivery to the Brain by an Implantable Smart Pump in a Sheep Model

Abstract

BACKGROUND AND OBJECTIVES: Intraventricular drug delivery enables the delivery of therapeutics to the central nervous system, while minimizing peripheral drug exposure and toxicity. However, currently used delivery devices cannot be controlled externally to adjust their output during delivery. Here, the authors investigated the performance of a conceptually novel device designed to metronomically deliver a drug to the cerebrospinal fluid in a manner that can be adjusted wirelessly from an external controller. METHODS: Six sheep were subcutaneously implanted in the shoulder region with a drug delivery pump and a catheter connecting to the brain ventricles. Three groups of 2 sheep received low, medium, and high dosages of metronomic methotrexate (MTX) over several weeks, while kept mobile outdoors in a pen. MTX dosages were adjusted from a wireless external controller, and intraventricular MTX concentrations were measured in regular intervals with an Ommaya reservoir. RESULTS: Over the course of this 12-week study, sheep showed no signs of toxicity. MTX measurements in the cerebrospinal fluid confirmed that the pump remained responsive to external control and able to deliver drug in an adjustable, metronomic fashion. CONCLUSION: This implantable pump system enables external control of drug output, so that the resulting intraventricular drug concentrations can continuously be maintained within the therapeutic range.