title: A phase I clinical trial of the effect of belinostat on the pharmacokinetics and pharmacodynamics of warfarin.
abstract: OBJECTIVE
  Belinostat is a potent small molecule inhibitor that exerts its antitumor effect through inhibition of histone deacetylase. The purpose of this study was to evaluate the pharmacokinetics and pharmacodynamics of warfarin (as a reference drug metabolized by CYP2C9) in the presence and absence of belinostat.
  
  
  METHODS
  We conducted a phase I, single-center, open-label, drug-drug interaction study between belinostat and warfarin. In part I, patients were given warfarin 5 mg orally (day-14 and 3) and belinostat 1000 mg/m(2) (days 1 through 5). Patients receiving benefit continued belinostat on days 1 through 5 every 21 days until disease progression, unacceptable toxicity, or per patient preference.
  
  
  RESULTS
  A total of 18 patients were treated. With belinostat, the least-squared means for maximum concentration (C max), area under the curve0-∞, and area under the curve0-t of R-warfarin were slightly increased. However, for the more potent S-warfarin isomer, the same parameters were primarily contained within the pre-specified equivalence limits of 0.80 and 1.25, indicating there was no statistically significant interaction between S-warfarin and belinostat. The most common adverse events were nausea, vomiting, and fatigue. Three grade 3 adverse events (diarrhea 5.6 %, nausea 5.6 %, and vomiting 5.6 %) were thought to be treatment related. Progression-free survival ranged from 0.2 to 13.8 months in all patients.
  
  
  CONCLUSIONS
  Belinostat did not significantly affect the pharmacokinetics and pharmacodynamics of warfarin, indicating no clinically relevant effect on the enzymatic activity of CYP2C9.
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA. Neeraj.Agarwal@hci.utah.edu.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.
authors.forename: Jordan P
authors.initials: JP
authors.lastname: McPherson
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bailey
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.
authors.forename: Sumati
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Werner
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, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Bailey
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005221:Fatigue / Q000139:chemically induced*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced*; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D014859:Warfarin; D065729:Cytochrome P-450 CYP2C9; C487081:belinostat
keywords: Belinostat; CYP2C9; Drug–drug interaction; PXD101; Pharmacokinetics; Phase I study