In Vivo Disposition and Pharmacokinetics and In Vitro Inhibition and Induction Profiles of Saxagliptin, a Potent Inhibitor of Dipeptidyl Peptidase 4, in Human

ONGLYZA™, (saxagliptin, BMS-477118) is a potent dipeptidyl peptidase (DPP4) inhibitor indicated for the treatment of type 2 diabetes mellitus. In this study, the pharmacokinetics and disposition of [¹⁴C]saxagliptin were determined following administration of a single 50 mg, 91.5 µCi oral dose to 6 healthy male subjects. Saxagliptin was rapidly absorbed with a Tmax of approximately 0.5 h. Thereafter, both saxagliptin and total radioactivity (TRA) concentrations declined rapidly with elimination half-life values of < 3 h. Saxagliptin and 5-hydroxysaxagliptin (M2), an active metabolite, were the most prominent drug-related components in the plasma; together they accounted for the majority of the AUC of circulating radioactivity. Parent drug and M2 were also the prominent drug-derived components in urine, while M2 was a prominent fecal metabolite. Approximately 97% of the administered radioactivity was recovered within 7 days post-dose, of which 74.9%, and 22.1% were excreted in the urine and feces, respectively. The parent compound and M2 comprised approximately 24% and 44% of the excreted dose, respectively, indicating that saxagliptin was highly metabolized and the primary pathway for metabolism of saxagliptin was hydroxylation of the adamantyl group to form M2. Formation of other hydroxylated metabolites, along with glucuronidation, and sulfation were minor pathways. Neither saxagliptin nor M2 inhibited or induced CYP enzymes, in vitro, suggesting that saxaliptin has low potential to affect the clearance of co-administered drugs that are substrates for CYP enzymes.