Absorption, metabolism, and excretion of [14C]ponatinib after a single oral dose in humans

• Published in: Cancer chemotherapy and pharmacology Vol. 79; no. 3; pp. 507 - 518
• Main Authors: Ye, Yihua E., Woodward, Caroline N., Narasimhan, Narayana I.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2017; Springer Nature B.V
• Subjects: Adult; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; Biotransformation; Cancer Research; Dealkylation; Feces - chemistry; Glucuronides - metabolism; Half-Life; Healthy Volunteers; Humans; Hydroxylation; Imidazoles - metabolism; Imidazoles - pharmacokinetics; Intestinal Absorption; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Male; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original; Original Article; Pharmacology/Toxicology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Pyridazines - metabolism; Pyridazines - pharmacokinetics; Pharmacokinetics; Ponatinib; Human metabolism; Radiolabeled
• DOI: 10.1007/s00280-017-3240-x
• ISSN: 0344-5704

Purpose 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 [ 14 C]ponatinib in healthy subjects. Methods A single 45-mg [ 14 C]ponatinib dose was administered orally to six healthy male volunteers, and absorption, metabolism, and excretion were assessed. Results 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. Conclusions Ponatinib was readily absorbed in humans, metabolized through multiple pathways and was eliminated mostly in feces.