Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects.

摘要

Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved for the treatment of severe COPD. The pharmacological effect is mediated mainly by its active metabolite roflumilast N-oxide. OBJECTIVE: This doubleblind, 2-period cross-over study was conducted to investigate the potential effects of concomitant roflumilast on pharmacokinetics and pharmacodynamics of warfarin and vice versa. MATERIALS AND METHODS: A total of 24 healthy adults was enrolled into the study. Once-daily oral doses of roflumilast (500 mug) or placebo were given for 12 days, with subjects receiving both treatments one after the other; single oral doses of (R,S)-warfarin (25 mg) were administered on Day -14 and Day 8 of both periods. Warfarin enantiomer concentrations, prothrombin time (PT), and clotting factor activity (Factor VII, only) as well as concentrations of roflumilast and roflumilast N-oxide were measured in plasma. RESULTS: There was no clinically relevant pharmacokinetic or pharmacodynamic interaction between warfarin and roflumilast. Exposure over 120 h (area under the curve, AUC0-120) with "Test" (warfarin plus roflumilast) and "Reference" (warfarin plus placebo) treatment for Factor VII (geometric mean ratio 102.1% (90% confidence interval: 99.7 - 104.7%)) and excess AUC0-120 for PT (99.3% (92.3 - 106.9%)) were unchanged. CONCLUSIONS: Pharmacokinetic parameters including maximum plasma concentration (Cmax) and AUC0-infinity of (R)-, (S)-warfarin, roflumilast, and roflumilast N-oxide were unaffected by co-administration.