Singh Dave, Scuri Mario, Collarini Sara, Vezzoli Stefano, Mariotti Fabrizia, Muraro Annamaria, Acerbi Daniela
Medicines Evaluation, University Of Manchester, University Hospital of South Manchester, Manchester, UK.
Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
Int J Chron Obstruct Pulmon Dis. 2017 Jul 7;12:2001-2014. doi: 10.2147/COPD.S137659. eCollection 2017.
An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 μg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 μg once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 μg. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV) area under the curve (AUC) and peak FEV, with a trend toward greater efficacy with higher GB dose. All adverse events were mild-moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose-response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV on Day 7 (primary) were 115, 142 and 136 mL for GB 12.5, 25 and 50 μg BID, respectively (all <0.001). GB 25 and 50 μg BID were superior (<0.05) to GB 12.5 μg BID for pre-dose morning FEV on Day 8. For this endpoint, GB 25 and 50 μg BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV peak and AUC with all GB doses and placebo (all <0.001). All adverse events were mild-moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 μg BID is the optimal dose in patients with COPD.
长效毒蕈碱拮抗剂格隆溴铵（GB）的超微制剂正在研发中，用于慢性阻塞性肺疾病（COPD），与二丙酸倍氯米松和富马酸福莫特罗联合使用——即“固定三联疗法”。这项分为两部分的研究在中重度COPD患者中进行，采用随机、双盲、安慰剂对照：第1部分：单剂量递增，GB 12.5、25、50、100或200μg与安慰剂对照；第2部分：重复给药（7天），四周期交叉，GB 12.5、25或50μg每日两次（BID）与安慰剂对照，并有一个开放标签扩展阶段，在此阶段所有患者接受每日一次18μg的噻托溴铵。在所有五个周期的第8天早晨，患者还接受12μg福莫特罗。在研究第1部分中，招募了27名患者。所有GB剂量均使1秒用力呼气量（FEV）曲线下面积（AUC）和FEV峰值较基线显著增加，且GB剂量越高，疗效有增加趋势。所有不良事件的严重程度为轻至中度，GB组的发生率低于安慰剂组，且无剂量反应关系的证据。在研究第2部分中，招募的38名患者中有34名完成了研究。在第7天（主要观察指标），GB 12.5、25和50μg BID与安慰剂相比，12小时谷值FEV的调整后平均差异分别为115、142和136 mL（均<0.001）。在第8天给药前早晨FEV方面，GB 25和50μg BID优于GB 12.5μg BID（<0.05）。对于该观察指标，GB 25和50μg BID也优于噻托溴铵。与第7天相比，所有GB剂量组和安慰剂组加用福莫特罗均使第8天FEV峰值和AUC显著增加（均<0.001）。所有不良事件的严重程度为轻至中度，且无剂量相关关系的迹象。本研究提供了超微GB BID支气管舒张作用、安全性和药代动力学的初步证据。总体而言，结果表明GB 25μg BID是COPD患者的最佳剂量。
