title: Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.
abstract: The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immediate-release tablets of roflumilast 250 or 500 microg as single (day 1) and as repeated, once-daily doses for 8 days (days 5-12). Dose-adjusted point estimates and 90% confidence intervals of test (500 microg)/reference (250 microg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N-oxide. Repeated oral dosing with roflumilast 250 and 500 microg once daily was well tolerated.
authors.affiliation: Department of Clinical Development Strategy, ALTANA Pharma AG, Konstanz, Germany.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bethke
authors.forename: Gabriele M
authors.initials: GM
authors.lastname: Böhmer
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hauns
authors.forename: Richard
authors.initials: R
authors.lastname: Fux
authors.forename: Klaus
authors.initials: K
authors.lastname: Mörike
authors.forename: Michael
authors.initials: M
authors.lastname: David
authors.forename: Dietrich
authors.initials: D
authors.lastname: Knoerzer
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Wurst
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Gleiter
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D019540:Area Under Curve; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D013058:Mass Spectrometry; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast