TRTH-07. THE DISTRIBUTION, CLEARANCE AND TOXICITY OF PANOBINOSTAT ADMINISTERED TO JUVENILE RAT AND PIG BRAINSTEM BY CONVECTION ENHANCED DELIVERY

The pan-histone deacetylase inhibitor panobinostat has preclinical efficacy against DIPG and the oral formulation has entered a phase one clinical trial. However, panobinostat does not cross the blood brain barrier in humans. Convection enhanced delivery (CED) is a novel neurosurgical drug delivery...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2017-06, Vol.19 (suppl_4), p.iv52-iv53
Main Authors: Singleton, WGB, Bienemann, AS, Wooley, M, Johnson, D, Lewis, O, Wyatt, MJ, White, LJ, Damment, SJP, Killick-Cole, C, Asby, DJ, Gill, SS
Format: Article
Language:English
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Summary:The pan-histone deacetylase inhibitor panobinostat has preclinical efficacy against DIPG and the oral formulation has entered a phase one 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 DIPG. We investigated the toxicity, distribution and clearance of a water-soluble formulation of panobinostat in small and large animal models of CED. 30 juvenile male Wistar rats received panobinostat administered to the pons by CED at increasing concentration and were compared to animals that received vehicle alone. Clinical observation continued for two weeks. Animals were sacrificed at 72 hours or two weeks following treatment and the brains were subjected to neuropathological analysis. A further 6 animals received panobinostat by CED to the striatum and were sacrificed zero, two or six hours after infusion, their brains explanted and snap-frozen. Brainstem drug concentration was determined by LC-MS/MS. Large animal toxicity was investigated using a clinically relevant MRI guided translational porcine model of CED using a drug delivery system designed for human use. 30 μM panobinostat was administered to the ventral pons of two juvenile Large White/Landrace-cross pigs and subject to clinical and neuropathological analysis compared to control after one or two weeks. Drug distribution was determined by LC-MS/MS in porcine white and gray matter immediately after CED. There were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 μM in both small and large animal models. The half-life of panobinostat in rat brain after CED was 3 hours and the drug was observed to distribute in porcine white and gray matter with a volume infusion/distribution ratio of two and three respectively. CED of water-soluble panobinostat warrants investigation in children with DIPG.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/nox083.219