title: A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and various degrees of hepatic function.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of hepatic function.
  
  
  METHODS
  Patients with advanced solid malignancies, acceptable bone marrow and renal function, and normal or impaired hepatic function, per NCI-ODWG criteria, were eligible. Initially patients received a single oral dose of 30 mg panobinostat for a 1-week pharmacokinetic study (core phase). Subsequently, patients received thrice-weekly panobinostat for as long as beneficial (extension phase safety assessment). Core phase serial blood samples for panobinostat and metabolite BJB432 assay were collected pre-dose and up to 96 h post-dose.
  
  
  RESULTS
  Twenty-five patients were enrolled, median age 58 years (range 45-76). Fifteen patients had hepatic dysfunction (8 mild, 6 moderate, and 1 severe). Reductions in panobinostat plasma clearance were 30 and 51 %, with concomitant 43 and 105 % increase in exposure, for patients with mild and moderate hepatic dysfunction, respectively. Median peak plasma concentrations were 1.4-(mild) and 1.8-(moderate) fold higher than the normal group. Hepatic impairment did not alter panobinostat absorption with Tmax unchanged at 2 h. Geometric mean ratios of BJB432 to panobinostat plasma AUC0-∞ were similar in patients with normal, mild, or moderate hepatic impairment. Safety data were consistent with known safety profile of panobinostat in patients with advanced cancers and normal liver function.
  
  
  CONCLUSIONS
  Despite increased plasma exposure, patients with mild or moderate hepatic dysfunction could be safely treated with the same starting dose of panobinostat as patients with normal hepatic function, with careful monitoring and dose adjustments as required.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands, m.slingerland@lumc.nl.
authors.forename: Marije
authors.initials: M
authors.lastname: Slingerland
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hess
authors.forename: Sally
authors.initials: S
authors.lastname: Clive
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Per
authors.initials: P
authors.lastname: Sandstrom
authors.forename: Niklas
authors.initials: N
authors.lastname: Loman
authors.forename: Maria G
authors.initials: MG
authors.lastname: Porro
authors.forename: Song
authors.initials: S
authors.lastname: Mu
authors.forename: Edward
authors.initials: E
authors.lastname: Waldron
authors.forename: Sue-Zette
authors.initials: SZ
authors.lastname: Valera
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000077767:Panobinostat; D016896:Treatment Outcome; D014839:Vomiting
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat