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

Abstract

PurposePonatinib 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.MethodsA single 45-mg [14C]ponatinib dose was administered orally to six healthy male volunteers, and absorption, metabolism, and excretion were assessed.Results86.6 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.ConclusionsPonatinib was readily absorbed in humans, metabolized through multiple pathways and was eliminated mostly in feces.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-017-3240-x) contains supplementary material, which is available to authorized users.

Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase

“…The 4‐methyl benzamide ring in our first‐generation compounds and also in ponatinib could pose a possible metabolic liability, whereby the benzylic hydrogens are oxidized. Ponatinib was found to be hydroxylated by liver enzymes, and some of this hydroxylation could occur at the 4‐methyl position on the benzamide ring . We therefore explored the possibility of removing this potential metabolic liability with a halogen or bulkier alkyl group, such as ethyl (compounds 9 – 16 , Figure ).…”

Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol

“…Of particular interest were the drugs masitinib and ponatinib, as they were shown to be potent modulators of multiple biomolecules associated with DHCR24 beyond Des, including 7-DHD and 24-DHL. The effect of these two TKIs are likely translatable to human populations, as the concentrations utilized in this project for masitinib and ponatinib are similar to their known C max values of 51 nM and 145 nM, respectively (44,45). In contrast, the other TKI utilized in this study, imatinib, may be even more efficacious, as it can be tolerated in humans at blood concentrations in the micromolar range (34).…”

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…Ponatinib 68 biotransformation pathways primarily involve hydrolysis of the amide bond in plasma, hydroxylation, and piperazine N ‐demethylation . CYP1A1‐mediated aromatic hydroxylation of ponatinib was shown using recombinant enzyme incubations and mono‐ and dihydroxylated metabolites 69 and 70 were identified in humans (Figure ). GSH adduct formation was observed, with recombinant enzymes, in parallel to the disappearance of hydroxylated ponatinib metabolites, suggesting that the initial reaction was an epoxidation.…”

“…Moreover, ponatinib might also lead to aldehyde RM, since a carboxylic acid and a glucurono‐conjugated carboxylic acid have been detected in human plasma and/or excreta. The former arises through N ‐dealkylation of the piperazine ring, and the latter through oxidation of the piperazine methyl group . However, to the best of our knowledge, no other study has been undertaken to reassess CYP MBI.…”

“…The former arises through N-dealkylation of the piperazine ring, and the latter through oxidation of the piperazine methyl group. 64 However, to the best of our knowledge, no other study has been undertaken to reassess CYP MBI.…”