title: A phase I study to determine the pharmacokinetics and urinary excretion of belinostat and metabolites in patients with advanced solid tumors.
abstract: OBJECTIVE
  Belinostat is an inhibitor of histone deacetylase enzymes, resulting in DNA repair inhibition and apoptosis. Present data are lacking to provide dosing recommendations in renal insufficiency. The purpose of this trial was to assess the pharmacokinetics (PK) of belinostat and belinostat metabolites in plasma and urine.
  
  
  METHODS
  This was a phase I, single-center, open-label, two-part study. In Part I, patients received single-agent belinostat 1000 mg/m2. Blood and urine samples were collected at pre-specified time points to determine PK of belinostat and metabolites and their elimination in urine. In Part II, patients were permitted to continue belinostat in 21-day cycles on Days 1 through 5 until disease progression, unacceptable toxicity, or according to patient preference.
  
  
  RESULTS
  A total of nine patients with advanced solid tumors were treated. Median tmaxfor belinostat was observed 10 min after the start of infusion. Concentrations of belinostat rapidly declined with a t1/2of 2.9 h. The mean fraction of belinostat excreted unchanged in urine was 0.926 %. The metabolites belinostat glucuronide and 3-ASBA represented the largest fractions of belinostat dose excreted in urine (30.5 and 4.61 %, respectively), while renal excretion appeared to be a minor route of elimination for the parent belinostat (<1 %). The most common adverse events were nausea, fatigue, and diarrhea. One Grade 3 adverse event (constipation) was thought to be treatment related.
  
  
  CONCLUSIONS
  Urinary elimination of parent belinostat was minimal, although a combined 36.7 % of belinostat metabolites were excreted in urine. Since these metabolites are primarily inactive, belinostat may not require dosage adjustment in renal dysfunction.
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bailey
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
authors.forename: Jordan P
authors.initials: JP
authors.lastname: McPherson
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Bailey
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Werner
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
authors.forename: Sumati
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Batten
authors.affiliation: Spectrum Pharmaceuticals, Irvine, CA, USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Reddy
authors.affiliation: Spectrum Pharmaceuticals, Irvine, CA, USA.
authors.forename: Gajanan
authors.initials: G
authors.lastname: Bhat
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA. Neeraj.Agarwal@hci.utah.edu.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001711:Biotransformation; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C487081:belinostat
keywords: Belinostat; Elimination; HDAC inhibitor; Metabolites; PXD101; Pharmacokinetics