The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery

William G.B. Singleton, Alison S. Bienemann, Max Woolley, David Johnson, Owen Lewis, Marcella J. Wyatt, Stephen J.P. Damment, Lisa J. Boulter, Clare L. Killick-Cole, Daniel J. Asby, Steven S. Gill*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

18 Citations (Scopus)
1 Downloads (Pure)

Abstract

OBJECTIVE The pan-histone 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. METHODS 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 μM to the ventral pons of 2 juvenile Large White-Landrace 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. RESULTS 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 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. CONCLUSIONS CED of water-soluble panobinostat, up to a concentration of 30 μM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.

Original languageEnglish
Pages (from-to)288-296
Number of pages9
JournalJournal of Neurosurgery: Pediatrics
Volume22
Issue number3
Early online date1 Jun 2018
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • Brainstem
  • Convection-enhanced delivery
  • DIPG
  • Half-life
  • HDAC inhibitor
  • Histone deacetylase inhibitor
  • Oncology
  • Panobinostat
  • Toxicity
  • Translation
  • Volume of distribution

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