Abediterol (AZD0548)
作用机制：吸入，（uttra）长效β2-肾上腺素能激动剂（Laba）
临床前药理学
Abediterol is a potent and selective β2-adrenoceptor agonist. Its sustained duration of action (24 hours) and tolerable safety profile are compatible with once daily dosing. Functional pharmacology studies performed in both isolated animal tissues and in human bronchial rings demonstrate that abediterol is a full agonist with both high potency and β2-adrenoceptor selectivity comparable to formoterol and salmeterol, respectively. The onset of action of abediterol in isolated human bronchial rings is more rapid than that of salmeterol. Abediterol was shown to be a LABA in in vitro functional studies and in in vivo studies, where a long duration of action was demonstrated
Safety and tolerability
A total of 12 studies have been conducted with abediterol (as napadisylate salt,) alone or in fixed dose combination (FDC), with mometasone furoate or AZD7594 (velsecorat). In these studies, 409 subjects have received one or more doses of abediterol delivered by oral inhalation. The anticipated therapeutic dose is in the range 0.5–2 μg. Adverse effects related to primary pharmacology have been observed at all abediterol dose levels, but most notably at doses of 10 μg or greater. The earlier clinical studies investigating higher dose levels of abediterol (2.5 μg to 50 μg), showed dose-dependency in the frequency of adverse events (AEs) typically associated with β2-adrenoceptor stimulation (eg. tremor, palpitations, restlessness, nervousness and dizziness). The clinical studies conducted to date have also demonstrated dose-dependent increases in heart rate and QTcF at doses ≥5 μg, and changes in levels of serum glucose and potassium at doses of ≥25 μg.
Chronic GLP toxicology studies in rat (6 mo) & dog (9 mo) and reproductive toxicology in rat & rabbit have been completed.
临床药理学
Abediterol pharmacokinetics (PK) after oral inhalation is characterised by very low systemic exposure with plasma levels within the pg/ml or sub-pg/ml range.
在患有哮喘的患者中，吸入单剂量从0.05μg至25μg的嗜酸盐与支气管扩张相关，所述支气管扩张效应快速[在一秒钟（FEV1）中从强迫呼气量的基线增加了统计学上显着增加了5分钟后剂量]。通常会观察到FEV1中的最大平均增加约3至4小时后剂量。FEV1中基线的统计学显着增加持续到剂量后至少24小时。
In patients with COPD single inhaled doses of abediterol 0.625 μg, 2.5 μg, 5 μg and 10 μg were also associated with marked and sustained bronchodilation (statistically significant increases in FEV1 compared with placebo from 15 minutes to 36 hours post dose).
Linear PK is observed. Abediterol exhibits relatively high plasma protein binding of 87.1% in humans. Main metabolic route identified in vitro is via CYP450, with the CYP3A4 isoform mediating 99% of the overall oxidative metabolism. The risk of drug-drug interaction with abediterol as a perpetrator has been assessed in vitro. The likelihood of a clinically important hepatic or intestinal interaction is regarded as low.
适合和exclusions
Suitable for any patient requiring treatment with a rapidly-acting, long-duration maintenance bronchodilator. May also be suitable for acute use. In any patients with asthma, abediterol should be administered in combination with an inhaled corticosteroid, in line with requirements for other LABA-containing products.
Additional information
Clinical Trials
Publications for this compound
Initial Indication
Asthma
Route of administration
吸入