Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.

摘要

Objective: To investigate the effects of steady state erythromycin on the pharmacokinetics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide in healthy subjects. Both roflumilast and roflumilast N-oxide have similar intrinsic PDE4 inhibitory activity; the total PDE4 inhibition (tPDE4i) in humans is likely due to the combined effect of roflumilast and roflumilast N-oxide. Methods: Subjects (n = 16) received single oral roflumilast 500 microg once daily (Days 1 and 15), and repeated oral erythromycin 500 mg three times daily (Days 9 - 21). Percent ratios of Test/Reference (Reference: roflumilast alone; Test: roflumilast and steady-state erythromycin) were calculated for the geometric means and their 90% confidence intervals for systemic exposure (AUC), maximum concentration (Cmax) (roflumilast and roflumilast N-oxide), and apparent clearance of roflumilast. Results: After co-administration of erythromycin and roflumilast, the mean AUC and Cmax of roflumilast increased by 70% and 40%, respectively. The mean apparent clearance of roflumilast decreased from 8.2 l/h (Reference) to 4.8 l/h (Test). Steady-state erythromycin did not alter the mean AUC of roflumilast N-oxide, however, the mean Cmax decreased by 34%. The AUCroflumilast N-oxide/AUCroflumilast ratio decreased from 10.6 (Reference) to 6.4 (Test). Co-administration of erythromycin and roflumilast did not influence the integrated total exposure to roflumilast and roflumilast N-oxide, i.e. mean tPDE4i. No clinically relevant adverse events were observed during the study. Conclusions: Co-administration of erythromycin (a moderate CYP3A4 inhibitor) and roflumilast does not require dose adjustment of roflumilast.