Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity that may be beneficial in the treatment of COPD. Roflumilast and its metabolite, roflumilast N-oxide, are pharmacologically active. Patients with COPD often receive warfarin for control of cardiovascular co-morbidity. This study determined whether pharmacodynamic or pharmacokinetic interactions exist between oral roflumilast and oral warfarin.
In this double-blind, randomized, placebo-controlled crossover study, healthy adult male subjects (N=24; age 19 to 45 years) received either oral roflumilast 500μg or placebo once-daily for 12 consecutive days. All subjects were given each a single oral dose of warfarin sodium 25mg 14 days prior to roflumilast or placebo intake and on Day 8 concomitant with roflumilast or placebo. Washout periods between consecutive roflumilast or placebo treatments were 10 days. Serial blood samples were taken the day before and after warfarin administration. Prothrombin time, coagulation factor VII activity, and plasma concentrations of roflumilast, roflumilast N-oxide, and R- and S-warfarin were determined. Point estimates and 90% confidence intervals (CI) were used to evaluate pharmacokinetic equivalence between roflumilast co-administered with warfarin (Test, T) and placebo co-administered with warfarin (Reference, R). Safety parameters were monitored.
There was no effect of roflumilast on warfarin pharmacodynamics. Point estimate ratios (T/R) for AUC(0-120h) for prothrombin time and factor VII activity were 0.99 (90%CI: 0.92, 1.07) and 1.02 (90%CI: 1.00, 1.05), respectively. Similarly, roflumilast did not affect the pharmacokinetics of racemic warfarin. Equivalence ratios for AUC(0-¥) were 1.02 (90%CI: 1.00, 1.05) and 1.03 (90%CI: 1.01, 1.05) for R-warfarin and S-warfarin, respectively. Likewise, roflumilast had no effect on Cmax, tmax, or t1/2 of warfarin. The pharmacokinetics of roflumilast or roflumilast N-oxide were not influenced by the single concomitant warfarin administration. Co-administration of roflumilast and warfarin was well tolerated.
Oral, once-daily roflumilast 500μg can be safely co-administered together with warfarin without altering the pharmacodynamic or pharmacokinetic profile of warfarin.
In addition to roflumilast, patients may receive warfarin therapy without dose adjustments.
A. Huennemeyer, None.