title: Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates.
abstract: OBJECTIVE
  Histone deacetylases (HDAC) are involved in the regulation of gene transcription. Aberrant HDAC activity has been associated with tumorigenesis, and, therefore, HDACs are potential targets for the treatment of cancers, including tumors of the central nervous system (CNS). Belinostat is a novel, potent, pan-HDAC inhibitor with antiproliferative activity on a wide variety of tumor cell lines. We studied the cerebrospinal fluid (CSF) penetration of intravenous (IV) belinostat in a non-human primate model as a surrogate for blood:brain barrier penetration.
  
  
  METHODS
  Five adult rhesus monkeys received increasing doses of belinostat (10-60 mg/kg) as a 30-min IV infusion. Serial blood and CSF samples were collected over 48 h. Plasma and CSF concentrations of belinostat were quantified with an LC/MS/MS assay. Pharmacokinetic parameters were calculated using non-compartmental methods, and CSF penetration is expressed as the ratio of the area under the concentration-time curve (AUC) in CSF to the AUC in plasma.
  
  
  RESULTS
  Belinostat was cleared rapidly from plasma with a half-life of 1.0 h, a mean residence time of 0.47 h, and a clearance of 425 ml/min/m(2). CSF penetration of belinostat was limited. CSF drug exposure was <1% of plasma drug exposure and <10% of free (non-protein bound) plasma drug exposure.
  
  
  CONCLUSIONS
  IV belinostat is rapidly cleared from plasma and has limited penetration into the CSF.
authors.affiliation: National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA. warrenk@mail.nih.gov
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
authors.forename: Cindy
authors.initials: C
authors.lastname: McCully
authors.forename: Henrik
authors.initials: H
authors.lastname: Dvinge
authors.forename: Jette
authors.initials: J
authors.lastname: Tjørnelund
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Henri S
authors.initials: HS
authors.lastname: Lichenstein
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D013449:Sulfonamides
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C487081:belinostat