Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity, which may provide effective treatment of chronic obstructive pulmonary disease (COPD) and asthma. Both, roflumilast and its major metabolite, roflumilast N-oxide, are pharmacologically active. This study evaluated the pharmacokinetics of both, roflumilast and roflumilast N-oxide, and safety following single and repeated once-daily doses of oral roflumilast in healthy subjects.
This open-label, randomized, 2-period crossover study consisted of two treatment periods of 12 days each, separated by a 10- to 14-day washout period. During each treatment period, 19 healthy male subjects received oral roflumilast 250μg or 500μg once daily on Day 1 (single dose) and Days 5 to 12 (repeated dosing). Blood samples were collected on Days 1 and 12 of each treatment period. Adverse events, vital signs, and ECG were monitored throughout the study.
Roflumilast and roflumilast N-oxide exhibited dose-proportional pharmacokinetics after single and repeated once-daily dosing with roflumilast 250μg and 500μg. After repeated dosing with roflumilast 250μg and 500μg (in steady-state), geometric mean AUCs of roflumilast were 17.0μgxh/L and 33.7μgxh/L, respectively; for roflumilast N-oxide, the respective geometric mean AUCs were 179.8μgxh/L and 375.4μgxh/L. Similarly, Cmax of roflumilast and roflumilast N-oxide showed a dose-proportional response. Repeated administration of either dose showed no relevant influence on the geometric means of the terminal half-life (t1/2) of roflumilast (roflumilast 250μg: 16.0h; 500μg: 18.0h) and roflumilast N-oxide (roflumilast 250μg: 23.1h; 500μg: 21.2h). Roflumilast was well tolerated. The majority of adverse events was mild to moderate in intensity, transient in duration and were not of any clinical concern.
Roflumilast and roflumilast N-oxide showed dose-proportional pharmacokinetics after single and repeated oral administration of once-daily roflumilast 250μg and 500μg. Both roflumilast doses were well tolerated.
Roflumilast given at 250μg and 500μg exhibits dose-proportional pharmacokinetics. The long terminal half-life of roflumilast and its active N-oxide metabolite supports the convenient once-daily dosing for optimal anti-inflammatory therapy.
A. Huennemeyer, None.