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Multiple Doses of Sitagliptin, a Selective DPP-4 Inhibitor, Do Not Meaningfully Alter Pharmacokinetics and Pharmacodynamics of Warfarin

From Merck & Co, Inc, Rahway, New Jersey.

Sitagliptin is an orally active, highly selective dipeptidyl peptidase IV (DPP-4) inhibitor for treatment of type 2 diabetes mellitus. This randomized, open-label, 2-part, 2-period crossover study assessed pharmacokinetics/pharmacodynamics of warfarin in the presence/absence of multiple-dose sitagliptin. Twelve participants received treatments A and B separated by >7-day washout: treatment A involved coadministration of sitagliptin 200 mg/d for 11 days (days 1-11) and warfarin 30 mg on day 5, and treatment B involved warfarin 30 mg alone on day 1. R(+) warfarin, S(-) warfarin, and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. The geometric mean ratios (GMRs; warfarin + sitagliptin/warfarin alone) (90% confidence intervals [CIs]) were 0.99 (0.95, 1.03) and 0.95 (0.90, 1.02) for the AUC_0- of R(+) and S(-) warfarin, respectively. GMRs (warfarin + sitagliptin/warfarin alone) (90% CIs) were 0.89 (0.86, 0.93) and 0.89 (0.86, 0.92) for the C_max of R(+) and S(-) warfarin, respectively. INR AUC_{0-168 h} and INR_max GMRs were 1.01 (0.96, 1.06) and 1.08 (1.00, 1.17), respectively. Coadministration of sitagliptin and warfarin was generally well tolerated. Pharmacokinetics (AUC for R(+) and S(-) warfarin) and pharmacodynamics (INR of R(+) or S(-) warfarin) were not meaningfully altered following coadministration of multiple-dose sitagliptin and single-dose warfarin, indicating that no dosage adjustment for warfarin is necessary when coadministered with sitagliptin.

Key Words: Sitagliptin • warfarin • pharmacokinetics • pharmacodynamics

Address for reprints: D. Hamish Wright, PhD, Associate Director, Department of Clinical Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065; e-mail: hamish_wright{at}merck.com.

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