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

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.