title: Pharmacokinetics, metabolism, and excretion of (14)C-labeled belinostat in patients with recurrent or progressive malignancies.
abstract: BACKGROUND
  Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (50-70%), with renal excretion accounting for ~30-50%. A Phase 1 human mass balance study was conducted to identify species-dependent variations in belinostat metabolism and elimination.
  
  
  METHODS
  Patients received a single 30-min intravenous (i.v.) infusion of (14)C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography-tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m(2) on Days 1-5 every 21 days) was permitted.
  
  
  RESULTS
  Belinostat was extensively metabolized and mostly cleared from plasma within 8 h (N = 6), indicating that metabolism is the primary route of elimination. Systemic exposure for the 5 major metabolites was >20% of parent, with belinostat glucuronide the predominant metabolite. Mean recovery of radioactive belinostat was 94.5% ± 4.0%, with the majority excreted within 48 and 96 h in urine and feces, respectively. Renal elimination was the principal excretion route (mean 84.8% ± 9.8% of total dose); fecal excretion accounted for 9.7% ± 6.5%. Belinostat was well tolerated, with mostly mild to moderate adverse events and no treatment-related severe/serious events.
  
  
  CONCLUSIONS
  Mass balance was achieved (~95% mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites.
authors.affiliation: START Madrid-CIOCC Phase 1 Program, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Research and Development Department, Spectrum Pharmaceuticals, 157 Technology Drive, Irvine, CA, 92618, USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Reddy
authors.affiliation: START Madrid-CIOCC Phase 1 Program, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Valentina
authors.initials: V
authors.lastname: Boni
authors.affiliation: Nuclear Medicine Department, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Lina
authors.initials: L
authors.lastname: García-Cañamaque
authors.affiliation: Research and Development Department, Spectrum Pharmaceuticals, 157 Technology Drive, Irvine, CA, 92618, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Song
authors.affiliation: Onxeo, S.A., Paris, France.
authors.forename: Jette
authors.initials: J
authors.lastname: Tjornelund
authors.affiliation: Research and Development Department, Spectrum Pharmaceuticals, 157 Technology Drive, Irvine, CA, 92618, USA. mirim.choi@sppirx.com.
authors.forename: Mi Rim
authors.initials: MR
authors.lastname: Choi
authors.affiliation: Research and Development Department, Spectrum Pharmaceuticals, 157 Technology Drive, Irvine, CA, 92618, USA.
authors.forename: Lee F
authors.initials: LF
authors.lastname: Allen
mesh_terms: D000368:Aged; D002250:Carbon Radioisotopes / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011851:Radioactivity; D013449:Sulfonamides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D002250:Carbon Radioisotopes; D006877:Hydroxamic Acids; D013449:Sulfonamides; C487081:belinostat
keywords: Belinostat; Epigenetic biology; Histone deacetylase inhibitor (HDACi); Mass balance