Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, 08020, Barcelona, Spain.
Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain.
Respir Res. 2020 Sep 9;21(Suppl 1):211. doi: 10.1186/s12931-020-01470-5.
Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/β-adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma.
This was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts which evaluated escalating doses of navafenterol (50-2100 μg) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from pre-dose baseline in trough forced expiratory volume in 1 s (FEV) for each treatment period.
Sixteen patients were randomised; 15 completed treatment. Data from all 16 patients were analysed. The maximum tolerated dose was not identified, and all doses of navafenterol were well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were headache (n = 10, 62.5%) and nasopharyngitis (n = 7, 43.8%). No TEAEs were serious, fatal, or led to discontinuation, and no dose dependency was identified. Navafenterol demonstrated a dose-ordered bronchodilatory response with a rapid onset of action (within 5 min post-dose). Doses ≥200 μg resulted in improvements in trough FEV (mean change from baseline range 0.186-0.463 L) with sustained bronchodilation for 24-36 h. Plasma concentrations increased in a dose-proportional manner, peaking ~ 1 h post-dose, with a derived terminal elimination half-life of 15.96-23.10 h.
In this study navafenterol was generally well tolerated with a rapid onset of action which was sustained over 36 h.
ClinicalTrials.gov; No.: NCT02573155.
Navafenterol（AZD8871）是一种正在开发的用于治疗阻塞性气道疾病的吸入性长效双重药理学毒蕈碱拮抗剂/β-肾上腺素能受体激动剂（MABA）。在轻度哮喘患者中研究了 navafenterol 的安全性、耐受性、药效学和药代动力学。
这是一项随机、单盲、安慰剂对照、单递增剂量研究。患者随机分为两组，两组以交替方式评估 navafenterol 的递增剂量（50-2100μg），共三个治疗期。主要药效学终点是每个治疗期的预剂量基础值与谷值用力呼气 1 秒（FEV）的变化。
16 名患者被随机分配；15 名患者完成了治疗。对所有 16 名患者的数据进行了分析。未确定最大耐受剂量，所有剂量的 navafenterol均耐受良好。报告的最常见治疗后不良事件（TEAEs）是头痛（n=10，62.5%）和鼻咽炎（n=7，43.8%）。无 TEAEs 为严重、致命或导致停药，且未确定剂量依赖性。Navafenterol 表现出剂量有序的支气管扩张反应，起效迅速（给药后 5 分钟内）。剂量≥200μg 导致谷值 FEV 改善（从基线变化范围 0.186-0.463 L），24-36 小时持续支气管扩张。血浆浓度呈剂量比例增加，给药后约 1 小时达到峰值，推导的终末消除半衰期为 15.96-23.10 小时。
在这项研究中，navafenterol 通常具有良好的耐受性，起效迅速，持续时间超过 36 小时。
ClinicalTrials.gov；编号：NCT02573155。
