title: Absorption, metabolism, and excretion of [14C]ponatinib after a single oral dose in humans.
abstract: Ponatinib is a novel tyrosine kinase inhibitor (TKI) specifically designed to inhibit native and mutated BCR-ABL. In the United States, ponatinib has received accelerated approval for adults with T315I-positive chronic myeloid leukemia (CML) or T315I (gatekeeper mutation)-positive, Philadelphia chromosome-positive, acute lymphoblastic leukemia (Ph + ALL), and patients with CML or Ph + ALL for whom no other TKI therapy is indicated. The objective of this phase 1, mass balance study was to evaluate the absorption, metabolism, and excretion of [14C]ponatinib in healthy subjects.
  
  
  
  A single 45-mg [14C]ponatinib dose was administered orally to six healthy male volunteers, and absorption, metabolism, and excretion were assessed.
  
  
  
  86.6 and 5.4% of the dose was recovered in feces and urine, respectively, during days 0-14 postdose. Median time to maximal plasma radioactivity was 5 h and mean terminal elimination half-life of radioactivity was 66.4 h. Ponatinib and its inactive carboxylic acid metabolite M14, the two major circulating radioactive components, accounted for 25.5 and 14.9% of the radioactivity in 0-24 h pooled plasma, with elimination half-lives of 27.4 and 33.7 h, respectively. Major metabolites in urine were M14 and its glucuronides, which, together with other M14-derived metabolites, represented 4.4% of the dose; ponatinib was not detected in urine. In feces, major radioactive components were ponatinib, M31 (hydroxylation), M42 (N-demethylation), and four methylated products accounting for 20.5, 17.7, 8.3, and 8.4% of the radioactive dose, respectively.
  
  
  
  Ponatinib was readily absorbed in humans, metabolized through multiple pathways and was eliminated mostly in feces.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Lansdowne St, Cambridge, MA, 02139, USA.
authors.forename: Yihua E
authors.initials: YE
authors.lastname: Ye
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Lansdowne St, Cambridge, MA, 02139, USA.
authors.forename: Caroline N
authors.initials: CN
authors.lastname: Woodward
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Lansdowne St, Cambridge, MA, 02139, USA. narayana.narasimhan@ariad.com.
authors.forename: Narayana I
authors.initials: NI
authors.lastname: Narasimhan
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001711:Biotransformation; D003640:Dealkylation; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D006900:Hydroxylation; D007093:Imidazoles / Q000378:metabolism* / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D020719:Glucuronides; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib
keywords: Human metabolism; Pharmacokinetics; Ponatinib; Radiolabeled