Abediterol (AZD0548)

Mechanism of action: Inhaled, (ultra) long-acting β2-adrenoceptor agonist (LABA)


Preclinical pharmacology

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.


Clinical pharmacology

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.

In patients with asthma, inhaled single doses of abediterol from 0.05 μg to 25 μg were associated with bronchodilation which was rapid in onset [with statistically significant increases from baseline in forced expiratory volume in one second (FEV1) by 5 to 15 minutes post dose]. Maximal mean increases in FEV1 were generally observed approximately 3 to 4 hours post dose. Statistically significant increases from baseline in FEV1 were sustained until at least 24 hours post dose.

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.


Suitable for and 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

Inhalation