title: Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD.
abstract: GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties. This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14. MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only. GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.
authors.affiliation: University of Cape Town Lung Institute, George Street, Mowbray 7700, Cape Town, South Africa. Eric.Bateman@uct.ac.za
authors.forename: Eric D
authors.initials: ED
authors.lastname: Bateman
authors.forename: Oliver
authors.initials: O
authors.lastname: Kornmann
authors.forename: Claire
authors.initials: C
authors.lastname: Ambery
authors.forename: Virginia
authors.initials: V
authors.lastname: Norris
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068299:Salmeterol Xinafoate; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D000069447:Tiotropium Bromide; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D002219:Carbamates; D018727:Muscarinic Antagonists; D015363:Quinolones; D012602:Scopolamine Derivatives; C588122:batefenterol; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000069447:Tiotropium Bromide
keywords: Bi-functional molecule; COPD; MABA