Metabolism and Disposition of Cabozantinib in Healthy Male Volunteers and Pharmacologic Characterization of Its Major Metabolites

• Published in: Drug metabolism and disposition 2015-08, Vol.43 (8), p.1190-1207
• Main Authors: Lacy, Steven, Hsu, Bih, Miles, Dale, Aftab, Dana, Wang, Ronghua, Nguyen, Linh
• Format: Article
• Language: English
• Subjects: Adult; Anilides - pharmacokinetics; Anilides - toxicity; Animals; Area Under Curve; Bile Ducts - metabolism; Bile Ducts - physiology; Biotransformation; Blood Proteins - metabolism; Carrier Proteins - metabolism; Cytochrome P-450 Enzyme System - metabolism; Dogs; Erythrocytes - metabolism; Humans; Male; Middle Aged; Protein Binding; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - toxicity; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyridines - pharmacokinetics; Pyridines - toxicity; Rats; Tissue Distribution; Young Adult
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.115.063610

Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib l-malate containing 14C-cabozantinib (100 µCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N-oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies ≤1/10th of parent cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 (Kiapp = 4.6 and 1.1 µM, respectively). In an in vitro drug transporter panel, cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 µM, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 µM, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both cabozantinib and EXEL-1644 may represent potential for drug-drug interactions.