title: Unexpected high levels of vorinostat when combined with vinorelbine in patients with advanced cancer.
abstract: BACKGROUND
  This study was a multi-centre, dose-escalation trial in patients with advanced cancers. Primary objective was to determine maximum tolerated dose (MTD) of vorinostat, a competitive inhibitor of histone deacetylase (HDAC), in combination with vinorelbine. Secondary aims were to determine (1) corresponding pharmacokinetics, (2) safety of this regimen, and (3) impact of UGT1A1 and 2B17 polymorphisms on vorinostat pharmacokinetics.
  
  
  METHODS
  Starting dose of once daily oral vorinostat was 200 mg for 7 days every 21 days in combination with a 20-min intraveinous weekly infusion of vinorelbine 25 mg/m2, starting 4 hours after the first vorinostat dose. During cycle 1, blood samples were collected at day 1 for vorinostat and at days 1 and 8 for vinorelbine for pharmacokinetic evaluation.
  
  
  RESULTS
  Seven patients were included. Most of adverse events observed were mild (grades 0-2) and reversible after treatment discontinuation (hemotological toxicity, asthenia, diarrhea, dyspnea, fever, hyperglycemia and nausea). Two patients had a dose limiting toxicity at the first dose level that consisted of grade 3 hyperglycemia and vinorelbine administration was delayed. The first dose-level was considered as the MDT and therefore dose escalation was stopped. Mean vorinostat plasma AUC was higher than reported previously at a similar dose when used as single agent or in combination with other cytotoxics. There was no obvious vinorelbine-vorinostat interaction nor any correlation with UGT1A1 or 2B17 polymorphisms.
  
  
  CONCLUSIONS
  MDT of the combination was 200 mg oral vorinostat for 7 days in combination with 25 mg/m2 weekly vinorelbine. Severity of hyperglycemia was most likely related to unexpected high vorinostat exposures.
authors.affiliation: EA4553, Institut Claudius-Regaud and Universite de Toulouse, France. gandia_chu@yahoo.fr
authors.forename: Peggy
authors.initials: P
authors.lastname: Gandia
authors.forename: Cecile
authors.initials: C
authors.lastname: Arellano
authors.forename: Quentin
authors.initials: Q
authors.lastname: Chalret du Rieu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lochon
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.forename: Muriel
authors.initials: M
authors.lastname: Poublanc
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hennebelle
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D000077337:Vorinostat; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D006877:Hydroxamic Acids; D015778:Minor Histocompatibility Antigens; D014747:Vinblastine; D000077235:Vinorelbine; D000077337:Vorinostat; D000099148:UGT1A1 Enzyme; C500513:UGT2B17 protein, human