Li Qian, Wang Yiya, Liu Lingye, Ma Pengcheng, Ding Li
Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
Nanjing Clinical Tech Laboratories Inc., 18 Zhilan Road, Jiangning District, Nanjing, 211000, People's Republic of China.
Eur J Drug Metab Pharmacokinet. 2017 Jun;42(3):371-381. doi: 10.1007/s13318-016-0343-4.
Roflumilast is a selective, oral phosphodiesterase 4 inhibitor approved for the treatment of severe chronic obstructive pulmonary disease. The aim of this study was to evaluate the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy Chinese subjects, and the effects of gender and food on their respective pharmacokinetic profiles.
36 healthy Chinese subjects were recruited in a randomized, single-center, open-label, parallel group study and assigned to 0.25-, 0.375-, and 0.5-mg dose groups. The single-dose pharmacokinetic studies in fasting condition were carried out in all groups. Moreover, the food effect study and multiple-dose study were conducted in 0.375-mg dose group. Serial blood samples were collected over 168 h after dosing, and plasma concentrations of roflumilast and roflumilast N-oxide were determined using a validated LC-MS/MS method.
After oral administration of single doses of 0.25, 0.375 and 0.5 mg of roflumilast under fasting condition, the mean AUC for roflumilast was 21.7 ± 8.3, 29.8 ± 8.3 and 54.2 ± 21.3 ng·h/mL, respectively. Meanwhile the mean AUC for roflumilast N-oxide was 290 ± 103, 385 ± 107 and 673 ± 245 ng·h/mL, respectively. In the steady state after the multi-dose administration, the exposure to roflumilast in the subjects increased 20-40 %, and the exposure to roflumilast N-oxide increased about 169 %, compared to the single-dose administration. No statistically significant effect of gender on the disposition of roflumilast and roflumilast N-oxide was observed. Food had no effect on systemic exposure to roflumilast and roflumilast N-oxide in the subjects, but delayed the T of roflumilast by 0.9 h and reduced the C of roflumilast by approximately 20 %.
Based upon between-study comparison, peak and systemic exposure of roflumilast and roflumilast N-oxide were higher in Chinese than that in Caucasian subjects after oral administration of the same dose (i.e., 0.25 and 0.5 mg). It implies that the therapeutic dose for Chinese patients may be different from that for Caucasians, warranting further investigation.
罗氟司特是一种经批准用于治疗重度慢性阻塞性肺疾病的选择性口服磷酸二酯酶4抑制剂。本研究旨在评估罗氟司特及其N - 氧化物在健康中国受试者中的药代动力学，以及性别和食物对其各自药代动力学特征的影响。
36名健康中国受试者参与了一项随机、单中心、开放标签、平行组研究，并被分配到0.25毫克、0.375毫克和0.5毫克剂量组。所有组均进行了空腹条件下单剂量药代动力学研究。此外，在0.375毫克剂量组进行了食物影响研究和多剂量研究。给药后168小时内采集系列血样，采用经过验证的液相色谱 - 串联质谱法测定罗氟司特及其N - 氧化物的血浆浓度。
在空腹条件下口服单剂量0.25毫克、0.375毫克和0.5毫克罗氟司特后，罗氟司特的平均药时曲线下面积（AUC）分别为21.7±8.3、29.8±8.3和54.2±21.3纳克·小时/毫升。同时，罗氟司特N - 氧化物的平均AUC分别为290±103、385±107和673±245纳克·小时/毫升。多剂量给药后的稳态下，与单剂量给药相比，受试者中罗氟司特的暴露量增加了20% - 40%，罗氟司特N - 氧化物的暴露量增加了约169%。未观察到性别对罗氟司特及其N - 氧化物处置的统计学显著影响。食物对受试者中罗氟司特及其N - 氧化物的全身暴露无影响，但使罗氟司特的达峰时间（Tmax）延迟了0.9小时，并使罗氟司特的峰浓度（Cmax）降低了约20%。
基于研究间比较，口服相同剂量（即0.25毫克和0.5毫克）后，中国受试者中罗氟司特及其N - 氧化物的峰值和全身暴露高于白种人受试者。这意味着中国患者的治疗剂量可能与白种人不同，值得进一步研究。
