Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

ABSTRACT Objective: Vildagliptin is a potent and selective dipeptidyl peptidase‑IV (DPP‑4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of vildagliptin 100 mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg oral dose of warfarin sodium. Research design and methods: Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects. Results: The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of vildagliptin, R- and S‑warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for vildagliptin, R- and S‑warfarin maximum plasma concentration (Cmax) were also within the equivalence range 0.80–1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PTmax, 1.00 [90% CI 0.97, 1.04]; AUCPT, 0.99 [0.97, 1.01]) and international normalized ratios (INRmax, 1.01 [0.98, 1.05]; AUCINR, 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80–1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication. Conclusions: Co-administration of warfarin with vilda­gliptin did not alter the pharmacokinetics and pharmaco­dynamics of R- or S‑warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.