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


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 (PT(max), 1.00 [90% CI 0.97, 1.04]; AUC(PT), 0.99 [0.97, 1.01]) and international normalized ratios (INRmax, 1.01 [0.98, 1.05]; AUC(INR), 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.
He
Yan-Ling
YL
Exploratory Development, Novartis Institutes for Biomedical Research, Cambridge, MA 02139-3584, USA. yanling.he@novartis.com
Sabo
Ron
R
Riviere
Gilles-Jacques
GJ
Sunkara
Gangadhar
G
Leon
Selene
S
Ligueros-Saylan
Monica
M
Rosenberg
Mitchell
M
Dole
William P
WP
Howard
Dan
D
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006262:Health; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077597:Vildagliptin; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000925:Anticoagulants; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D014859:Warfarin; D000077597:Vildagliptin; D000218:Adamantane