Pharmacokinetics of single- and multiple-dose roflumilast: an open-label, three-way crossover study in healthy Chinese volunteers
Received 2 July 2018
Accepted for publication 22 October 2018
Published 26 November 2018 Volume 2018:12 Pages 4047—4057
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Sukesh Voruganti
Jie Huang,1,2,* Cheng-xiao Fu,1,2,* Xiao-yan Yang,1,2 Chan Cui,1,2 Shuang Yang,1,2 Yun Kuang,1,2 Cheng-xian Guo,1,2 Pei Hu,3 Qi Pei,2,4 Guo-ping Yang1,2
1Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Center for Clinical Drug Evaluation, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100032, People’s Republic of China; 4Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China
*These authors contributed equally to this work
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 (Cmax) of roflumilast (Tmax) was 0.25–2.0 hours; thereafter, the concentration declined, with a mean half-life (t1/2) of 19.7–20.9 hours over the range of 0.25–0.50 mg. As for roflumilast N-oxide, the mean t1/2 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 Cmax 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 Cmax and AUC values was observed at doses ranging from 0.25 to 0.50 mg.
Keywords: pharmacokinetics, roflumilast, roflumilast N-oxide, healthy volunteer, phosphodiesterase 4 inhibitor
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