Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males.

center dot Sitagliptin is an oral antihyperglycaemic agent that improves glycaemic control by inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that is principally responsible for inactivation of incretins. Incretins are endogenous peptide hormones that support glycaemic homeostasis through glucose-dependent stimulation of insulin secretion by pancreatic beta-cells and suppression of glucagon secretion by alpha-cells. center dot Pharmacokinetic properties of sitagliptin and inhibition of plasma DDP-4 by sitagliptin have been characterized previously in young, normoglycaemic, non-Japanese adult males and in other non-Japanese subjects. It was found in these studies that doses of at least 100 mg once daily produced nearly complete inhibition of DPP-4 over 24 h. WHAT THIS STUDY ADDS center dot The findings from this study suggest that the pharmacokinetic and pharmacodynamic (i.e. plasma DPP-4 inhibition) properties of sitagliptin in Japanese subjects are not substantially different from responses in non-Japanese subjects. center dot Consumption of a standardized traditional Japanese breakfast prior to dose ingestion did not alter plasma sitagliptin concentrations to a clinically meaningful extent. center dot Oral administration of sitagliptin at approved doses provided nearly complete inhibition of DPP-4 over an interval of 24 h. The findings support once daily dosing with sitagliptin in Japanese patients with type 2 diabetes. AIMS Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400 mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48 h post dose and plasma DPP-4 inhibition from 0-24 h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6 h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14 h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin >= 50 mg resulted in weighted average DPP-4 inhibition from 0-24 h post-dose > 94% (without correction, > 78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.