Safety, Pharmacokinetics (PK), Metabolism, and Mass Balance of [¹⁴C]-AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl Tyrosine Kinase, in Healthy Subjects.

Background: AMN107, a selective and potent inhibitor of Bcr-Abl tyrosine kinase signaling, has demonstrated activity against imatinib resistant forms of Bcr-Abl in patients with chronic myelogenous leukemia at daily oral doses of ≥200 mg in a phase I clinical trial. These studies also showed dose proportional systemic exposure to drug in the 50 - 200 mg range, but progressively less than proportional increases and higher variability in drug exposure with daily doses >200 mg. The present study in healthy volunteer subjects was conducted to determine the safety, PK, metabolism, and mass balance of AMN107 to aid in the understanding of the processes that may contribute to the drug’s PK behavior and potentially impact safety and efficacy.

Methods: 4 male volunteer subjects (age 23 to 46 years) received, after an overnight fast, a single oral 400 mg dose of AMN107 radiolabeled with carbon-14 to a specific activity of 0.25 μCi/mg. Quantitative urine and fecal collections, and sequential blood and serum collections for determination of levels of total radioactivity, unchanged AMN107, and AMN107 metabolites, were obtained for up to 7 days post dose. Subjects were in good health based on medical history, clinical laboratory and vital signs assessment at baseline, and were monitored for safety during the 7 days study duration and an end-of-study evaluation on day 14 post dose.

Results: There were no clinically significant changes from baseline in laboratories, vital signs, and medical examination. Mild headache was noted in 3/4 subjects which resolved without intervention. Complete recovery (97.9% of dose) was achieved within 7 days, 4.4% in urine and 93.5% in feces (69% unchanged AMN107), indicating incomplete oral absorption amounting to at least 31% of dose, and rapid elimination and no significant retention of drug and metabolites in the body. Peak serum concentrations of total radioactivity and AMN107 were observed at about 4 h post dose. AMN107 represented >75% of the total serum radioactivity at all time points monitored post dose. The terminal elimination half-life of AMN107 was about 16 hours. The major circulating metabolite, a carboxylic acid derivative of AMN107, accounting for approximately 7% of serum exposure and 4% of dose elimination in feces, was formed via an AMN107 carbinol derivative, which accounted for approximately 5% of serum exposure and 4% of dose elimination in feces. Several minor metabolites resulting from oxidation of AMN107 were also detected. Metabolite profiles were similar in whole blood and serum.

Conclusions: AMN107 administered as a single 400 mg oral dose to healthy volunteer subjects was safe and well tolerated. Complete recovery of single dose suggests absence of drug retention with chronic treatment. The elimination rate of AMN107 supports once or twice daily dosing, the latter representing a potential approach to increasing the absorption of the daily dose.