Bethke T D, Hartmann M, Hünnemeyer A, Lahu G, Gleiter C H
Nycomed GmbH, Konstanz, Germany.
Int J Clin Pharmacol Ther. 2011 Aug;49(8):491-9. doi: 10.5414/cp201556.
Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved in the European Union for the treatment of severe COPD. Roflumilast and its metabolites are mainly (70% of total radioactivity) eliminated via the kidneys as glucuronides. The potential impact of renal impairment on the pharmacokinetics of roflumilast and its active main metabolite roflumilast N-oxide were characterized.
Patients (n = 12) with severe renal impairment (creatinine clearance CL(CR) < 30 ml/ min/1.73 m²; otherwise healthy) and matched (sex, age, weight, and height) healthy control subjects (n = 12; CL(CR) > 80 ml/min/1.73 m²) were enrolled into an open-label, parallelgroup study. Single dose (500 μg, p.o.) pharmacokinetics and safety/tolerability of roflumilast and roflumilast N-oxide were compared between both groups.
A minor decrease of exposure (area under the plasma concentration-time curve from time zero to infinity (AUC(0-∞)), maximum plasma concentration (C(max))) and a small increase in elimination half-life (t(1/2)) of roflumilast (-1%; -6%; +19%, respectively) and roflumilast N-oxide (-%; ND; +30%, respectively) were observed in renally impaired patients compared with healthy subjects. No relevant differences in safety and tolerability were observed between groups.
The pharmacokinetic changes observed in patients with renal impairment are of small magnitude without clinical importance. A dose adjustment or a change in the administration interval of roflumilast is not necessary in patients with renal impairment.
罗氟司特是一种新型的口服活性选择性磷酸二酯酶4抑制剂，最近在欧盟被批准用于治疗重度慢性阻塞性肺疾病（COPD）。罗氟司特及其代谢产物主要（占总放射性的70%）以葡糖醛酸苷的形式经肾脏排泄。本研究旨在明确肾功能损害对罗氟司特及其活性主要代谢产物N-氧化罗氟司特药代动力学的潜在影响。
将严重肾功能损害（肌酐清除率CL(CR) < 30 ml/ min/1.73 m²；其他方面健康）的患者（n = 12）和匹配的（性别、年龄、体重和身高）健康对照者（n = 12；CL(CR) > 80 ml/min/1.73 m²）纳入一项开放标签、平行组研究。比较两组单次口服剂量（500 μg）罗氟司特和N-氧化罗氟司特的药代动力学及安全性/耐受性。
与健康受试者相比，肾功能损害患者中罗氟司特（分别为-1%；-6%；+19%）和N-氧化罗氟司特（分别为-%；未检出；+30%）的暴露量（血浆浓度-时间曲线从零到无穷大的面积（AUC(0-∞)）、最大血浆浓度（C(max)））略有降低，消除半衰期（t(1/2)）略有延长。两组间在安全性和耐受性方面未观察到相关差异。
肾功能损害患者中观察到的药代动力学变化幅度较小，无临床意义。肾功能损害患者无需调整罗氟司特的剂量或给药间隔。
