Effects of Duloxetine on the Pharmacodynamics and Pharmacokinetics of Warfarin at Steady State in Healthy Subjects

This study evaluated the pharmacodynamics and pharmacokinetics of once-daily dosing of warfarin at steady state when taken concomitantly with once-daily doses of duloxetine. Healthy subjects with a stable international normalized ratio (INR) of 1.5 to 2.0 on an individualized fixed dose of warfarin (2-9 mg) in period 1 received daily warfarin and duloxetine (60 mg for 14 days [n = 15] or 60 mg for 4 days, then 120 mg for 10 days [n = 15]) in period 2. Across the 14-day period when warfarin was coadministered with duloxetine, the least squares mean INR changes from baseline (warfarin alone) ranged from -0.05 to +0.07, and the 90% confidence intervals ranged from -0.12 to +0.14. Following coadministration of warfarin with 60 mg duloxetine, but not with 120 mg duloxetine, there was a statistically significant prolongation in bleeding time compared to warfarin alone. For both R- and S-warfarin, the 90% confidence interval for the geometric mean ratios of area under the curve (AUC(tau,ss)) and maximum plasma concentrations (C(max,ss)) between warfarin administered alone and with 60 or 120 mg duloxetine were contained within the bioequivalence limits of 0.8 to 1.25. In conclusion, duloxetine had no clinically or statistically significant effect on the pharmacodynamics or pharmacokinetics of warfarin at steady state.