Drollmann Anton, Brown Matthew, Sechaud Romain, Perry Sheryl, Hara Hisanori, Jones Ieuan, Febbraro Salvatore
Int J Clin Pharmacol Ther. 2014 May;52(5):369-80. doi: 10.5414/CP202034.
QVA149 is a dual bronchodilator, containing a fixed-dose combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium, for the treatment of chronic obstructive pulmonary disease (COPD). Here we assess the potential of QVA149 (440/200 μg) at 4-fold the therapeutic dose for causing cardiac pharmacodynamic (PD) effects.
This double-blind, randomized study estimated the time-matched largest heart rate (HR) change and average HR change (over 24 hours) from baseline for QVA149 vs. placebo in healthy subjects. Similar analyses were done for QVA149 vs. indacaterol 600 μg, glycopyrronium 200 μg, and salmeterol 200 μg. The time-matched and average change from baseline in QT interval corrected for HR using Fridericia's formula (QTcF), effects on serum potassium and blood glucose, pharmacokinetic (PK) parameters, and safety were also assessed.
Of 50 subjects randomized, 43 completed the study. QVA149, when compared with placebo, showed the time-matched largest mean increase and decrease in HR of 5.69 bpm and -2.51 bpm, respectively, and average HR change from baseline of 0.62 bpm. QVA149 showed no tachycardic potential compared with indacaterol and no relevant tachycardic effect compared with glycopyrronium. No consistent differences were seen in the time-matched largest mean change and average change from baseline in QTcF for QVA149 vs. other treatments. There were no relevant effects of QVA149 on serum potassium and blood glucose. There was no apparent PK/PD relationship between the observed exposures to indacaterol and glycopyrronium in QVA149 on HR and QTcF. There were no deaths or serious adverse events.
Overall, short-term administration of QVA149 showed a good cardiovascular safety and tolerability profile in healthy subjects.
QVA149是一种双支气管扩张剂，含有长效β2受体激动剂茚达特罗和长效毒蕈碱拮抗剂格隆溴铵的固定剂量组合，用于治疗慢性阻塞性肺疾病（COPD）。在此，我们评估QVA149（440/200μg）在4倍治疗剂量下引起心脏药效学（PD）效应的可能性。
这项双盲、随机研究估计了健康受试者中QVA149与安慰剂相比，与基线相比在时间匹配时最大心率（HR）变化和平均HR变化（24小时内）。对QVA149与600μg茚达特罗、200μg格隆溴铵和200μg沙美特罗进行了类似分析。还评估了使用弗里德里西亚公式（QTcF）校正HR后的QT间期从基线的时间匹配和平均变化、对血清钾和血糖的影响、药代动力学（PK）参数以及安全性。
随机分组的50名受试者中，43名完成了研究。与安慰剂相比，QVA149在时间匹配时最大平均HR增加和减少分别为5.69次/分钟和-2.51次/分钟，平均HR从基线变化为0.62次/分钟。与茚达特罗相比，QVA149没有心动过速的可能性，与格隆溴铵相比没有相关的心动过速效应。QVA149与其他治疗相比，在时间匹配时最大平均变化和从基线的平均变化中，QTcF没有一致的差异。QVA149对血清钾和血糖没有相关影响。在QVA149中观察到的茚达特罗和格隆溴铵暴露量与HR和QTcF之间没有明显的PK/PD关系。没有死亡或严重不良事件。
总体而言，在健康受试者中短期给予QVA149显示出良好的心血管安全性和耐受性。
