title: Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects.
abstract: OBJECTIVE
  This study evaluated the effects of chronic hepatic impairment on the single-dose pharmacokinetics (PK) of the tyrosine kinase inhibitor ponatinib.
  
  
  METHODS
  Subjects (n = 16) had Child-Pugh class A (mild, n = 6), B (moderate, n = 6), or C (severe, n = 4) hepatic impairment and were matched with healthy controls (n = 8). Each subject received a single oral dose of ponatinib 30 mg under fasting conditions, and PK parameters were assessed in blood samples collected through 96 h post-dose.
  
  
  RESULTS
  Ponatinib maximum plasma concentrations (C max) were observed after 5-6 h in Child-Pugh A, Child-Pugh B, and healthy subjects, and after ~3 h in Child-Pugh C subjects. The estimated % geometric mean ratios for C max, area under the plasma concentration-time curves from time zero to last observation (AUC0-t ) and to infinity (AUC0-∞) suggested a slightly lower exposure in Child-Pugh B (61.4, 89.1, and 90.6%, respectively) and Child-Pugh C subjects (62.8, 77.1, and 79.4%) versus healthy subjects. Child-Pugh A subjects had similar estimated % geometric mean ratio for C max (106.7%), and slightly greater estimated % geometric mean ratios for AUC0-t (133.0%) and AUC0-∞ (122.8%), versus healthy subjects. Mean elimination half-life was extended in subjects with hepatic impairment (43-47 vs 36 h). Ponatinib was generally well tolerated. A single serious AE (pancreatitis) in the Child-Pugh C group resolved with treatment.
  
  
  CONCLUSIONS
  As no major differences in ponatinib single-dose PK were observed in patients with hepatic impairment versus healthy subjects, a reduction of ponatinib starting dose in these patients is not necessary, but caution is recommended when administering ponatinib to these patients.
authors.affiliation: DMPK and Preclinical Safety, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA, narayana.narasimhan@ariad.com.
authors.forename: Narayana I
authors.initials: NI
authors.lastname: Narasimhan
authors.forename: David J
authors.initials: DJ
authors.lastname: Dorer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Davis
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Marbury
authors.forename: Daryl
authors.initials: D
authors.lastname: Sonnichsen
mesh_terms: D000328:Adult; D019540:Area Under Curve; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012449:Safety; D014018:Tissue Distribution
chemical_list: D007093:Imidazoles; D011724:Pyridazines; C545373:ponatinib