Kharidia J, Fogarty C M, Laforce C F, Maier G, Hsu R, Dunnington K M, Curry L, Baumgartner R A, Hanrahan J P
Sepracor Inc., Marlborough, MA, USA.
Pulm Pharmacol Ther. 2008 Aug;21(4):657-62. doi: 10.1016/j.pupt.2008.03.003. Epub 2008 Apr 7.
Arformoterol is a single-isomer (R,R-formoterol) nebulized long-acting beta(2)-agonist approved for use in patients with chronic obstructive pulmonary disease (COPD). Exposure (plasma concentrations of (R,R)-formoterol) and forced expiratory volume in 1s (FEV(1)) were compared for 15 microg nebulized arformoterol and 12 and 24 microg racemic formoterol (containing 6 and 12 microg (R,R)-formoterol, respectively) delivered by dry powder inhaler (DPI).
An open-label, randomized, three-way crossover study in 39 subjects with COPD (FEV(1) 1.4L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15 microg) and racemic formoterol DPI (12 and 24 microg) for 14 days. Plasma concentrations of (R,R)- and (S,S)-formoterol were determined on days 1 and 14 of each treatment period. Airway function efficacy endpoints included the percent change in trough FEV(1) from baseline on day 14 of each treatment period.
At steady state, exposure to (R,R)-formoterol was similar following nebulized 15 microg arformoterol (C(max): 6.5 pg/mL; AUC(0-tau): 56.5 pgh/mL) and 12 microg racemic formoterol DPI (C(max): 6.2 pg/mL; AUC((0-)(tau)()): 46.3 pgh/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for C(max) and AUC((0-)(tau)()) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 microg racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: C(max) (10.8 pg/mL) and AUC((0-)(tau)()) (83.6 pgh/mL). Detectable (S,S)-formoterol was consistently measured only after treatment with racemic formoterol. The mean percent increase in trough FEV(1) was 19.1% in the arformoterol group, and 16.0% and 18.2% in the 12 and 24 microg racemic formoterol groups, respectively. Changes in (R,R)-formoterol concentrations over time paralleled changes in FEV(1).
In this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 microg arformoterol and 12 microg racemic formoterol DPI, and 40% lower than 24 microg racemic formoterol DPI. There was no evidence of chiral interconversion following treatment with arformoterol. Finally, temporal changes in airway function in all treatment groups corresponded to changes in (R,R)-formoterol plasma concentrations.
阿福特罗是一种单异构体（R，R - 福莫特罗）雾化吸入的长效β₂受体激动剂，已被批准用于慢性阻塞性肺疾病（COPD）患者。比较了15μg雾化吸入阿福特罗与通过干粉吸入器（DPI）递送的12μg和24μg消旋福莫特罗（分别含有6μg和12μg（R，R） - 福莫特罗）的暴露量（（R，R） - 福莫特罗的血浆浓度）和第1秒用力呼气量（FEV₁）。
对39例COPD患者（FEV₁为1.4L，占预测值的44.4%）进行了一项开放标签、随机、三交叉研究。每日两次的治疗包括雾化吸入阿福特罗（15μg）和消旋福莫特罗DPI（12μg和24μg），为期14天。在每个治疗周期的第1天和第14天测定（R，R） - 和（S，S） - 福莫特罗的血浆浓度。气道功能疗效终点包括每个治疗周期第14天FEV₁谷值相对于基线的变化百分比。
在稳态时，雾化吸入15μg阿福特罗（Cmax：6.5pg/mL；AUC₀ - τ：56.5pgh/mL）和12μg消旋福莫特罗DPI（Cmax：6.2pg/mL；AUC₀ - τ：46.3pgh/mL）后，（R，R） - 福莫特罗的暴露量相似。这两种治疗方法的Cmax和AUC₀ - τ的几何平均比值（90%置信区间）分别为0.91（0.76，1.09）和1.16（1.00，1.35）。使用24μg消旋福莫特罗DPI治疗导致（R，R） - 福莫特罗的剂量成比例增加：Cmax（10.8pg/mL）和AUC₀ - τ（83.6pgh/mL）。仅在使用消旋福莫特罗治疗后持续检测到可检测到的（S，S） - 福莫特罗。阿福特罗组FEV₁谷值的平均增加百分比为19.1%，12μg和24μg消旋福莫特罗组分别为16.0%和18.2%。（R，R） - 福莫特罗浓度随时间的变化与FEV₁的变化平行。
在本研究中，雾化吸入15μg阿福特罗和12μg消旋福莫特罗DPI后，（R，R） - 福莫特罗的血浆暴露量相似，且比24μg消旋福莫特罗DPI低40%。没有证据表明阿福特罗治疗后存在手性相互转化。最后，所有治疗组气道功能的时间变化与（R，R） - 福莫特罗血浆浓度的变化相对应。
