{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:27:22Z","timestamp":1791358042232,"version":"4.3.1"},"reference-count":32,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,9]]},"abstract":"\n OBJECTIVE<\/jats:title>\n The pan\u2013histone deacetylase inhibitor panobinostat has preclinical efficacy against diffuse intrinsic pontine glioma (DIPG), and the oral formulation has entered a Phase I clinical trial. However, panobinostat does not cross the blood-brain barrier in humans. Convection-enhanced delivery (CED) is a novel neurosurgical drug delivery technique that bypasses the blood-brain barrier and is of considerable clinical interest in the treatment of DIPG.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n The authors investigated the toxicity, distribution, and clearance of a water-soluble formulation of panobinostat (MTX110) in a small- and large-animal model of CED. Juvenile male Wistar rats (n = 24) received panobinostat administered to the pons by CED at increasing concentrations and findings were compared to those in animals that received vehicle alone (n = 12). Clinical observation continued for 2 weeks. Animals were sacrificed at 72 hours or 2 weeks following treatment, and the brains were subjected to neuropathological analysis. A further 8 animals received panobinostat by CED to the striatum and were sacrificed 0, 2, 6, or 24 hours after infusion, and their brains explanted and snap-frozen. Tissue-drug concentration was determined by liquid chromatography tandem mass spectrometry (LC-MS\/MS). Large-animal toxicity was investigated using a clinically relevant MRI-guided translational porcine model of CED in which a drug delivery system designed for humans was used. Panobinostat was administered at 30 \u03bcM to the ventral pons of 2 juvenile Large White\u2013Landrace cross pigs. The animals were subjected to clinical and neuropathological analysis, and findings were compared to those obtained in controls after either 1 or 2 weeks. Drug distribution was determined by LC-MS\/MS in porcine white and gray matter immediately after CED.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n There were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 \u03bcM in both small- and large-animal models. The half-life of panobinostat in rat brain after CED was 2.9 hours, and the drug was observed to be distributed in porcine white and gray matter with a volume infusion\/distribution ratio of 2 and 3, respectively.<\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS<\/jats:title>\n CED of water-soluble panobinostat, up to a concentration of 30 \u03bcM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.<\/jats:p>\n <\/jats:sec>","DOI":"10.3171\/2018.2.peds17663","type":"journal-article","created":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T09:55:32Z","timestamp":1527846932000},"page":"288-296","source":"Crossref","is-referenced-by-count":83,"title":["The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery"],"prefix":"10.3171","volume":"22","author":[{"given":"William G. 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