Oliver Amanda, VanBuren Sandi, Allen Ann, Hamilton Melanie, Tombs Lee, Inamdar Amir, Kempsford Rodger
GlaxoSmithKline, Uxbridge, United Kingdom.
GlaxoSmithKline, King of Prussia, Pennsylvania.
Clin Ther. 2014 Jun 1;36(6):928-939.e1. doi: 10.1016/j.clinthera.2014.03.014. Epub 2014 Apr 30.
Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β2-agonist.
We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β2-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma.
In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0-4 hours]) parameters on day 14.
Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study.
Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.
哮喘是一种困扰全球数百万儿童的慢性疾病。短效β2受体激动剂缓解药物和吸入性糖皮质激素（ICS）维持疗法是有效的治疗方法；然而，许多儿童在使用短效β2受体激动剂和ICS治疗后仍未得到控制，在这种情况下，指南建议加用长效β2受体激动剂。
我们旨在研究长效β2受体激动剂维兰特罗（VI）与糠酸氟替卡松（FF）通过ELLIPTA干粉吸入器（葛兰素史克公司，英国伦敦）联合给药，用于5至11岁持续性哮喘儿童的安全性、耐受性、药代动力学（PK）和药效学（PD）特性。
在这项随机、双盲、重复给药、双向交叉研究中，先回顾了8至11岁哮喘儿童的数据，然后是5至7岁哮喘儿童的数据。患者每天早晨接受一次FF/VI（100/25μg）或FF（100μg）治疗，持续14天，随后有≥7天的洗脱期，之后换用另一种治疗方法再治疗14天；研究持续时间≤11周。主要终点为不良事件（AE）、临床实验室指标、呼气峰值流速、最大心率、血压和心电图参数。次要终点包括第14天的PK（AUC0 - 4、Cmax）和PD（血清钾[0 - 4小时]、血清皮质醇[0 - 12小时]和葡萄糖[0 - 4小时]）参数。
26名儿童被随机分组（58%为男孩；平均年龄8.1岁）。未观察到主要终点有临床显著变化。分别有5名患者在FF/VI和FF治疗中报告了4次和2次AE。FF/VI或FF治疗后，FF的AUC0 - 4（1.02[0.86 - 1.22]）和FF的Cmax（0.98[0.65 - 1.48]）的几何平均比值（90%CI）相似。对于血清葡萄糖（0 - 4小时）浓度，FF/VI与FF相比差异为0.50 mM（95%CI，0.19 - 0.82 mM）；其他PD参数未观察到差异。没有AE被判定为严重或与治疗相关。FF的PK特征似乎未被VI改变，也不受年龄或性别的影响。由于测量是在非空腹患者中进行的，血清葡萄糖水平升高的意义难以判断。结果只能与活性治疗进行比较，并且由于该单中心研究患者数量少，推广能力有限。
在这个小样本的、经过挑选的5至11岁、大多为白种人/高加索人种的持续性哮喘儿童群体中，使用ELLIPTA干粉吸入器每日一次重复给予100/25μg的FF/VI与100μg的FF耐受性相当。
