title: Local and systemic effects of inhaled AZD9164 compared with tiotropium in patients with COPD.
abstract: There is still a need for new agents which improve upon the therapeutic index of tiotropium, the current standard of care for many patients with chronic obstructive pulmonary disease (COPD). We examined in patients with COPD the efficacy of single doses of AZD9164, an M(3)-selective muscarinic antagonist, to identify an appropriate dose-range for future studies. COPD patients (n = 28) inhaled AZD9164 (100, 400 and 1200 μg), tiotropium (18 μg) and placebo at 5 study centre visits (Clinicaltrials.gov identifier NCT00939211). The effects of these test drugs on average (E(av)), peak (E(max)) and trough (E(22-26)) forced expiratory volume in one second (FEV(1)) were assessed, as were systemically-mediated effects and the safety and exposure of single doses of AZD9164. AZD9164 100, 400 and 1200 μg caused increases in FEV(1) to peak effects of 12, 17 and 12% above baseline respectively, following an initial transient and dose-related fall in FEV(1) and associated increase in mild respiratory symptoms such as cough. Bronchodilation was maintained overnight, with minimal FEV(1) decline. AZD9164 400 and 1200 μg produced larger effects than tiotropium on E(22-26) (p < 0.05; both doses) while AZD9164 400 μg also had larger effects on E(max) (p = 0.001) and E(av) (p < 0.05). There were no serious adverse events and statistically significant systemic effects were observed only with AZD9164 1200 μg. AZD9164 may improve upon the therapeutic index of tiotropium, increasing the magnitude and duration of lung function improvements without increasing systemically-mediated adverse events. The initial bronchoconstrictor effect of AZD9164 requires further investigation.
authors.affiliation: Department of Respiratory Medicine and Allergology, University Hospital, Getingevägen 4, SE-221 85 Lund, Sweden. leif.bjermer@med.lu.se
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.forename: Thomas
authors.initials: T
authors.lastname: Bengtsson
authors.forename: Carin
authors.initials: C
authors.lastname: Jorup
authors.forename: Jan
authors.initials: J
authors.lastname: Lötvall
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011812:Quinuclidines / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors; D012602:Scopolamine Derivatives / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D000069447:Tiotropium Bromide
chemical_list: C570585:AZD9164; D001993:Bronchodilator Agents; D010880:Piperidines; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide