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Dose-Proportional Intraindividual Single- and Repeated-Dose Pharmacokinetics of Roflumilast, an Oral, Once-Daily Phosphodiesterase 4 Inhibitor

From the Department of Clinical Development Strategy (Dr Bethke), Department of Exploratory Medicine (Dr Hermann, Dr Hauns), Department of Metabolism and Pharmacokinetics (Dr David), Department of Pharmacometrics and Pharmacokinetics (Dr Knoerzer), and Department of Clinical Development Operations and Science (Dr Wurst), ALTANA Pharma AG, Konstanz, Germany, and the Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany (Dr Böhmer, Dr Fux, Dr Mörike, Dr Gleiter).

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 µg 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 µg)/reference (250 µg) ratios for AUC and C_max 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 (C_max) exposure of roflumilast and roflumilast N-oxide. Repeated oral dosing with roflumilast 250 and 500 µg once daily was well tolerated.

Key Words: roflumilast • phosphodiesterase 4 inhibitor • healthy subjects • COPD • asthma

Address for reprints: Dr Christoph H. Gleiter, Abteilung Klinische Pharmakologie, Universitätsklinikum Tübingen, Otfried-Müller-Str. 45, 72076 Tübingen, Germany; e-mail: christoph.gleiter{at}med.uni-tuebingen.de.

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