Hermann Robert, Nassr Nassr, Lahu Gezim, Péterfai Eva, Knoerzer Dietrich, Herzog Rolf, Zech Karl, de Mey Christian
Exploratory Medicine, ALTANA Pharma AG, Konstanz, Germany.
Clin Pharmacokinet. 2007;46(5):403-16. doi: 10.2165/00003088-200746050-00003.
Roflumilast and its primary N-oxide metabolite are targeted phosphodiesterase 4 (PDE4) inhibitors with similar in vivo potency. Roflumilast is being developed for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease and asthma.
To investigate the effects of mild and moderate liver cirrhosis on the steady-state pharmacokinetics of roflumilast and roflumilast N-oxide.
Patients with mild (n = 8, Child-Pugh A) and moderate (n = 8, Child-Pugh B) liver cirrhosis and healthy subjects (n = 8) matched with patients with cirrhosis with regard to sex, age and bodyweight received oral roflumilast 250 microg once daily for 14 days. Blood samples were collected for 24 hours after the last dose on day 14. Steady-state plasma concentrations of roflumilast and roflumilast N-oxide were determined using a validated high-performance liquid chromatography with tandem mass spectrometry assay. The pharmacokinetics were compared between groups using ANOVA.
In patients with liver cirrhosis, the average total exposure (area under the plasma concentration-time curve from 0 to 24 hours [AUC(24)]) of roflumilast was approximately 51% (Child-Pugh A) and 92% (Child-Pugh B) higher than in healthy subjects. In contrast, roflumilast maximum plasma concentration (C(max)) was unaltered in Child-Pugh A patients and was increased by 27% in Child-Pugh B patients. Changes in the AUC(24) of roflumilast N-oxide were less distinct, with 24% and 41% increases and corresponding C(max) increases of 26% and 40% in Child-Pugh A and B patients, respectively, compared with healthy subjects. Overall, changes in average potency-corrected exposure to the sum of the free fractions of both compounds were estimated to result in approximately 26% and 46% increases in total PDE4 inhibitory capacity (tPDE4i) in Child-Pugh A and B patients, respectively, relative to healthy subjects. Roflumilast was well tolerated.
Mild and moderate liver cirrhosis resulted in distinct alterations of exposure to roflumilast but only in modest alterations of exposure to roflumilast N-oxide. The integrated exposure-weighted assessment of the observed pharmacokinetic changes of roflumilast and roflumilast N-oxide (tPDE4i) indicates modest average exposure increases to the sum of both compounds. These findings and the favourable tolerability profile suggest that roflumilast can be safely used in patients with mild and moderate liver cirrhosis without special precautions or dose adjustment.
罗氟司特及其主要的N - 氧化物代谢产物是靶向磷酸二酯酶4（PDE4）抑制剂，体内效价相似。罗氟司特正被开发用于治疗炎症性气道疾病，如慢性阻塞性肺疾病和哮喘。
研究轻度和中度肝硬化对罗氟司特及其N - 氧化物稳态药代动力学的影响。
轻度（n = 8，Child - Pugh A级）和中度（n = 8，Child - Pugh B级）肝硬化患者以及健康受试者（n = 8，在性别、年龄和体重方面与肝硬化患者匹配）每天口服一次250μg罗氟司特，共14天。在第14天最后一剂给药后24小时采集血样。采用经过验证的高效液相色谱 - 串联质谱分析法测定罗氟司特及其N - 氧化物的稳态血浆浓度。使用方差分析比较各组间的药代动力学。
在肝硬化患者中，罗氟司特的平均总暴露量（0至24小时血浆浓度 - 时间曲线下面积[AUC(24)]）在Child - Pugh A级患者中比健康受试者高约51%，在Child - Pugh B级患者中高约92%。相比之下，Child - Pugh A级患者的罗氟司特最大血浆浓度（C(max)）未改变，而Child - Pugh B级患者中增加了27%。罗氟司特N - 氧化物的AUC(24)变化不太明显，与健康受试者相比，Child - Pugh A级和B级患者分别增加24%和41%，相应的C(max)分别增加26%和40%。总体而言，相对于健康受试者，估计Child - Pugh A级和B级患者中两种化合物游离部分总和的平均效价校正暴露量变化分别导致总PDE4抑制能力（tPDE4i）增加约26%和46%。罗氟司特耐受性良好。
轻度和中度肝硬化导致罗氟司特暴露量有明显改变，但仅导致罗氟司特N - 氧化物暴露量有适度改变。对罗氟司特及其N - 氧化物观察到的药代动力学变化进行综合暴露加权评估（tPDE4i）表明两种化合物总和的平均暴露量有适度增加。这些发现以及良好的耐受性表明，罗氟司特可安全用于轻度和中度肝硬化患者，无需特殊预防措施或剂量调整。
