Purpose: To determine the pharmacokinetic properties of the common tablet of roflumilast administered in single and multiple oral doses in Chinese subjects.
Subjects and methods: Both the single- and multiple-dose studies included 12 adults (6 males and 6 females). In this single-center, open-label study, single doses of 0.25, 0.375, and 0.5 mg were administered using a randomized, three-way crossover design, and then, the 0.375 mg dose was continued for 11 days once daily. The pharmacokinetic parameters for roflumilast and roflumilast N-oxide were determined and the safety evaluation included adverse events assessed by monitoring, physical examination, vital sign tests, and clinical laboratory tests.
Results: After every single dose, the time to the maximum concentration (C max) of roflumilast (T max) was 0.25-2.0 hours; thereafter, the concentration declined, with a mean half-life (t 1/2) of 19.7-20.9 hours over the range of 0.25-0.50 mg. As for roflumilast N-oxide, the mean t 1/2 was 23.2-26.2 hours. The area under curve from the beginning to 24 hours (AUC0-24 h), the AUC until infinity (AUCinf), and the C max of roflumilast and roflumilast N-oxide increased in a dose-proportional manner. After multiple doses, the accumulation index (Rac) on the 11th day of the steady state was ~1.63 for roflumilast and 3.20 for roflumilast N-oxide. No significant sex differences were observed in the pharmacokinetic parameters of roflumilast and roflumilast N-oxide. In addition, there were no serious adverse events across the trial.
Conclusion: Roflumilast was safe and well-tolerated in healthy volunteers, and a linear increase in its C max and AUC values was observed at doses ranging from 0.25 to 0.50 mg.
Keywords: healthy volunteer; pharmacokinetics; phosphodiesterase 4 inhibitor; roflumilast; roflumilast N-oxide.