Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

• Published in: Drug metabolism and disposition Vol. 42; no. 5; pp. 918 - 931
• Main Authors: Smith, Bill J., Pithavala, Yazdi, Bu, Hai-Zhi, Kang, Ping, Hee, Brian, Deese, Alan J., Pool, William F., Klamerus, Karen J., Wu, Ellen Y., Dalvie, Deepak K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2014
• Subjects: Adult; Axitinib; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Feces - chemistry; Humans; Imidazoles - blood; Imidazoles - metabolism; Imidazoles - pharmacokinetics; Imidazoles - urine; Indazoles - blood; Indazoles - metabolism; Indazoles - pharmacokinetics; Indazoles - urine; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Middle Aged; Molecular Structure; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - urine; Protein-Tyrosine Kinases - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; hERG; ADME; DMSO; MCPBA; nOe; MS; VEGF; AUCinf; β-RAM; M+H; AUC; LC-MS/MS; 1D; t1/2; LC; Tmax; VEGFR; HUVEC; ESI; ng-eq; HPLC; ELISA
• DOI: 10.1124/dmd.113.056531
• ISSN: 0090-9556

The disposition of a single oral dose of 5 mg (100 μCi) of [14C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0–12 hours), identified as axitinib N-glucuronide (M7) and axitinib sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%–60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.