title: Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor.
abstract: OBJECTIVE
  Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat.
  
  
  METHODS
  Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward.
  
  
  RESULTS
  In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting.
  
  
  CONCLUSIONS
  Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. a.hamberg@erasmusmc.nl
authors.forename: Paul
authors.initials: P
authors.lastname: Hamberg
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Woo
authors.forename: Lin-Chi
authors.initials: LC
authors.lastname: Chen
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Porro
authors.forename: Lily
authors.initials: L
authors.lastname: Zhao
authors.forename: Wenkui
authors.initials: W
authors.lastname: Li
authors.forename: Diane
authors.initials: D
authors.lastname: van der Biessen
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Thomas
authors.initials: T
authors.lastname: Hengelage
authors.forename: Maja
authors.initials: M
authors.lastname: de Jonge
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017674:Hypophosphatemia / Q000097:blood / Q000378:metabolism; D007211:Indoles; D007654:Ketoconazole / Q000097:blood / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D000077767:Panobinostat; D010597:Pharmacogenetics; D018401:Sample Size
chemical_list: D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole