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

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-017-3240-x) contains supplementary material, which is available to authorized users.