title: Comparison of the bronchodilator and systemic effects of AZD3199, an inhaled ultra-long-acting β₂-adrenoceptor agonist, with formoterol in patients with asthma.
abstract: OBJECTIVE
  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 (E(max)) and average 22-26 h (E₂₂₋₂₆) forced expiratory volume in 1 second (FEV1). Serum potassium was evaluated by minimum (E(min)) and 0-4 h average (E(av)) 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 E(max) and AZD3199 (480 and 1920 µg) and formoterol (36 µg) significantly increased E(₂₂₋₂₆) versus placebo. Relative dose potency between AZD3199 and formoterol was 50-fold on the microgram scale with respect to E max and 11-fold with respect to E(₂₂₋₂₆). 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.
authors.affiliation: Department of Respiratory Medicine and Allergology, Skåne University Hospital, Getingevägen 4, 22185 Lund, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.forename: Johan
authors.initials: J
authors.lastname: Rosenborg
authors.forename: Thomas
authors.initials: T
authors.lastname: Bengtsson
authors.forename: Jan
authors.initials: J
authors.lastname: Lötvall
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001249:Asthma / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D003718:Denmark; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004983:Ethanolamines / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D011188:Potassium / Q000097:blood; D013548:Sweden; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C544523:AZD-3199; D058666:Adrenergic beta-2 Receptor Agonists; D018927:Anti-Asthmatic Agents; D052160:Benzothiazoles; D001993:Bronchodilator Agents; D004983:Ethanolamines; D011188:Potassium; D000068759:Formoterol Fumarate
keywords: AZD3199; asthma; bronchodilator; chronic obstructive pulmonary disease; ultra-long-acting β2-agonist