Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates.
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.
Warren
Katherine E
KE
National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA. warrenk@mail.nih.gov
McCully
Cindy
C
Dvinge
Henrik
H
Tjørnelund
Jette
J
Sehested
Maxwell
M
Lichenstein
Henri S
HS
Balis
Frank M
FM
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
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C487081:belinostat