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

摘要: 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 (Ph + ALL), patients CML Ph + ALL whom no other TKI therapy indicated. The objective of this phase 1, mass balance study was evaluate absorption, metabolism, excretion [14C]ponatinib in healthy subjects. A single 45-mg dose administered orally six male volunteers, were assessed. 86.6 5.4% recovered feces urine, respectively, during days 0–14 postdose. Median time maximal plasma radioactivity 5 h mean terminal elimination half-life 66.4 h. its inactive carboxylic acid metabolite M14, two major circulating radioactive components, accounted 25.5 14.9% 0–24 h pooled plasma, half-lives 27.4 33.7 h, respectively. Major metabolites urine M14 glucuronides, which, together M14-derived metabolites, represented 4.4% dose; not detected urine. feces, components ponatinib, M31 (hydroxylation), M42 (N-demethylation), four methylated products accounting 20.5, 17.7, 8.3, 8.4% dose, readily absorbed humans, metabolized through multiple pathways eliminated mostly feces.