AZD0548
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 demonstrated 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 twelve 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 received one or more doses of abediterol delivered by oral inhalation. The anticipated therapeutic dose was 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 >10μg. The earlier clinical studies investigating higher dose levels of abediterol (2.5μg to 50μg), showed dose-dependency in the frequency of adverse events (AEs) typically associated with β2-adrenoceptor stimulation (e.g. 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 ≥5μg, and changes in levels of serum glucose and potassium at doses of ≥25μg.
Chronic GLP toxicology studies in rat (6-month) & dog (9-month) 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 0.05μg to 25μg 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 for at least 24-hours post-dose.
In patients with COPD, single-inhaled doses of abediterol, (0.625μg, 2.5μg, 5μg and 10μg) 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 was observed. Abediterol exhibits relatively high plasma protein binding of 87.1% in humans. The main metabolic route identified in vitro is 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 and the likelihood of a clinically important hepatic or intestinal interaction is deemed as low.
Suitable for and exclusions
Suitable for any patient requiring treatment with a rapidly-acting, long-duration maintenance bronchodilator. AZD0548 may also be suitable for acute use. In patients with asthma, abediterol should be administered in combination with an inhaled corticosteroid, in line with the requirements for other LABA-containing products.
Mechanism of Action
Inhaled, (ultra) long-acting β2-adrenoceptor agonist (LABA)
Original Therapeutic Area
Respiratory & Immunology
CNS Penetrant
Low
Route of administration
Inhaled
Modality
Small Molecule
Additional Information
1. Ramos., et al. (2018).
Abediterol (LAS100977), an inhaled long-acting beta(2)-adrenoceptor agonist, has a fast association rate and long residence time at receptor. Eur J Pharmacol. Jan 15;819:89-97. doi: 10.1016/j.ejphar.2017.11.043.
