Pharmacokinetics of single- and multiple-dose roflumilast: an open-label, three-way crossover study in healthy Chinese volunteers

Abstract

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 (AUC _{0–24 h}), the AUC until infinity (AUC _inf), and the C _max of roflumilast and roflumilast N-oxide increased in a dose-proportional manner. After multiple doses, the accumulation index (R _ac) 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.