Multiple doses of sitagliptin, a selective DPP-4 inhibitor, do not meaningfully alter pharmacokinetics and pharmacodynamics of warfarin.
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-infinity) 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.
Department of Clinical Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. hamish_wright@merck.com
D Hamish
DH
Wright
Gary A
GA
Herman
Andrea
A
Maes
Qi
Q
Liu
Amy O
AO
Johnson-Levonas
John A
JA
Wagner
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011517:Prothrombin Time; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects*; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000925:Anticoagulants; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D014859:Warfarin; D000068900:Sitagliptin Phosphate