title: Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects.
abstract: This open, randomized, single-dose crossover study investigated effects of a high-fat meal on the pharmacokinetics of roflumilast and its major active N-oxide metabolite. Twelve healthy subjects received oral roflumilast 500 microg (2 x 250 microg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N-oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC(0-last), AUC(0-infinity), and C(max) of both compounds. After the meal, roflumilast C(max) (PE, 0.59; 90% CI, 0.49-0.70) was modestly reduced; N-oxide C(max) (PE, 0.95; 90% CI, 0.90-1.01) was unchanged. Roflumilast t(max) was delayed in fed state (2.0 +/- 0.4 hours) versus fasted state (1.0 +/- 0.2 hours); N-oxide t(max) was unaltered. No significant food effect on roflumilast AUC(0-last) (PE, 1.04; 90% CI, 0.90-1.21), AUC(0-infinity) (PE, 1.12; 90% CI, 1.00-1.25), and respective N-oxide AUCs (PE, 0.91; 90% CI, 0.79-1.04; PE, 0.99; 90% CI, 0.92-1.06) occurred. Because roflumilast N-oxide is the major contributor to roflumilast's overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.
authors.affiliation: Department of Clinical Pharmacology, ALTANA Pharma AG, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany. bernhard.hauns@altanapharma.com
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hauns
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hünnemeyer
authors.forename: Rolf
authors.initials: R
authors.lastname: Herzog
authors.forename: Dieter
authors.initials: D
authors.lastname: Hauschke
authors.forename: Karl
authors.initials: K
authors.lastname: Zech
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bethke
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000328:Adult; D000631:Aminopyridines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D004041:Dietary Fats / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006261:Headache / Q000175:diagnosis / Q000453:epidemiology; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D004041:Dietary Fats; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517734:roflumilast N-oxide