Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.
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.
Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, Germany. gezim.lahu@nycomed.com
G
G
Lahu
A
A
Huennemeyer
R
R
Herzog
N
N
McCracken
R
R
Hermann
M
M
Elmlinger
K
K
Zech
D000284:Administration, Oral; D000328:Adult; D000631:Aminopyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019540:Area Under Curve; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000009:adverse effects / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004917:Erythromycin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
D000631:Aminopyridines; D000900:Anti-Bacterial Agents; D001549:Benzamides; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C517734:roflumilast N-oxide