Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.
Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. Twenty healthy participants received roflumilast, 500 µg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 19. The safety and tolerability of all treatments were also assessed. In 19 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with roflumilast alone. For roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance.
Lahu
Gezim
G
Nycomed GmbH, Konstanz, Germany. gezim.lahu@nycomed.com
Nassr
Nassr
N
Herzog
Rolf
R
Elmlinger
Martin
M
Ruth
Peter
P
Hinder
Markus
M
Huennemeyer
Andreas
A
D000284:Administration, Oral; D000328:Adult; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D015365:Enoxacin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D015365:Enoxacin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C517734:roflumilast N-oxide