title: A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer.
abstract: OBJECTIVE
  Panobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important.
  
  
  METHODS
  This study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes. Patients received 60 mg DM alone on day 1, panobinostat at 20 mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography-tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat).
  
  
  RESULTS
  Panobinostat increased DM exposure by 64 % [geometric mean ratio (GMR), 1.64 (90 % confidence interval (CI), 1.17-2.31)] and DX exposure by 29 % (GMR, 1.29 [90 % CI, 1.10-1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold.
  
  
  CONCLUSIONS
  Safety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.
authors.affiliation: Princess Margaret Hospital, University Health Network, 5th Floor Room 110, 610 University Avenue, Toronto, ON, M5G 2M9, Canada, Ronald.feld@uhn.ca.
authors.forename: Ronald
authors.initials: R
authors.lastname: Feld
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Woo
authors.forename: Natasha
authors.initials: N
authors.lastname: Leighl
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: J Thaddeus
authors.initials: JT
authors.lastname: Beck
authors.forename: Lihui
authors.initials: L
authors.lastname: Zhao
authors.forename: Lucien
authors.initials: L
authors.lastname: Gazi
authors.forename: Thomas
authors.initials: T
authors.lastname: Hengelage
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Porro
authors.forename: Asha
authors.initials: A
authors.lastname: Nayak
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D003917:Dextrorphan / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000473:pathology*; D000077767:Panobinostat; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D003917:Dextrorphan; D003915:Dextromethorphan; D000077767:Panobinostat; D019389:Cytochrome P-450 CYP2D6