| Title | Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. | | Author(s) | Lahu G, Huennemeyer A, Herzog R, McCracken N, Hermann R, Elmlinger M, Zech K | | Institution | 1Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, 2University of Tuebingen, Institute for Toxicology, Pharmacy and Chemistry, Tuebingen, and 3Clinical Research Appliance, Radolfzell, Germany. | | Source | Int J Clin Pharmacol Ther 2009 Apr; 47(4):236-45. | | Abstract | 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 19356389 |
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