Pharmacodynamics of GSK961081, a bi-functional molecule,in patients with COPD |
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| Authors: | Eric D. Bateman Oliver Kornmann Claire Ambery Virginia Norris |
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| Affiliation: | 1. University of Cape Town Lung Institute, George Street, Mowbray 7700, Cape Town, South Africa;2. IKF Pneumologie Frankfurt, Clinical Research Centre Respiratory Diseases, Frankfurt am Main, Germany;3. Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline Uxbridge, UK;4. Emerging Markets Research and Development, GlaxoSmithKline, Brentford, UK;1. Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, route de Lennik 808, 1070 Brussels, Belgium;2. Department of Infectious Diseases, Hôpital Erasme, Université Libre de Bruxelles, route de Lennik 808, 1070 Brussels, Belgium;3. Department of Clinical Biochemistry, Hôpital Erasme, Université Libre de Bruxelles, route de Lennik 808, 1070 Brussels, Belgium;1. Medical Oncology, National Cancer Centre Singapore, Singapore;2. Laboratory of Clinical Pharmacology, National Cancer Centre Singapore, Singapore;3. Oncologic Imaging, National Cancer Centre Singapore, Singapore;4. Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore;5. School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore;6. Laboratory of Molecular Endocrinology, Cellular and Molecular Research National Cancer Centre Singapore, Singapore;7. Pathology department, Singapore General Hospital, Singapore;1. Anesthésie Réanimation, CHU Rangueil, Toulouse, France;2. Centre des brûlés, Centre hospitalier, Lyon, France;3. Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, Toulouse, France;1. Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy;2. Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King''s College London, London, UK |
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| 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. |
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| Keywords: | Bi-functional molecule COPD MABA |
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