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Comparison of the bronchodilator and systemic effects of AZD3199, an inhaled ultra-long-acting β2-adrenoceptor agonist, with formoterol in patients with asthma

Objectives: Pharmacologically mediated bronchodilation is important in the management of asthma, and is primarily achieved with β2-agonists. Novel compounds should preferably have a longer duration of action and a better systemic side effect profile than established alternatives at comparable peak bronchodilation. This single-dose crossover study was conducted to investigate and compare with formoterol the bronchodilatory and systemic effects, tolerability and safety of AZD3199, a novel ultra-long-acting β2-agonist (uLABA). Methods: Patients with asthma (n = 37) were randomized to receive AZD3199 (120, 480, 1920 µg), formoterol (9, 36 µg) or placebo inhaled via a Turbuhaler™. Bronchodilation was evaluated by maximum (Emax) and average 22–26 h (E22–26) forced expiratory volume in 1 second (FEV1). Serum potassium was evaluated by minimum (Emin) and 0–4 h average (Eav) determined from serial measurements. AZD3199 and formoterol were compared on the basis of relative dose potency. Adverse events, clinical laboratory tests and physical examinations were markers for safety and tolerability, with plasma AZD3199 as the indicator of drug exposure. Results: All active treatments dose-dependently increased Emax and AZD3199 (480 and 1920 µg) and formoterol (36 µg) significantly increased E22–26 versus placebo. Relative dose potency between AZD3199 and formoterol was 50-fold on the microgram scale with respect to Emax and 11-fold with respect to E22–26. Small, dose-dependent effects on potassium, heart rate and QTc were seen after administration of AZD3199 compared with placebo. These well-known dose-related class effects of β2-agonists were mild. Notably, serum potassium suppression was less pronounced after AZD3199 compared with formoterol at similar bronchodilation. Overall, AZD3199 was well tolerated. Conclusions: AZD3199 480 µg and 1920 µg produced 24-hour bronchodilation. At comparable peak bronchodilator effect, AZD3199 was associated with a lower level of systemic side effects than formoterol. AZD3199 was well tolerated, with no safety concerns identified to preclude further investigation. ClinicalTrials.gov study identifier: NCT00736489