Activity of aclidinium bromide, a new long-acting muscarinic antagonist: A phase i study

Abstract

Aim: Aclidinium bromide is a muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This phase I trial in healthy subjects investigated the bronchodilator activity of aclidinium and its ability to reduce methacholine-induced bronchoconstriction. Methods: This double-blind, partial-crossover study randomized 12 subjects to treatment with single doses of aclidinium (50, 300 or 600 μg) or placebo. Drug activity was assessed for 24 h after administration by specific airway conductance (sGaw), airways resistance (Raw) and bronchial responsiveness (PC35 sGaw methacholine). Results: Aclidinium significantly increased sGaw compared with placebo at all assessments and doses (sGaw mean ± SD AUC (l kPa-1 h) for placebo 24.4 ± 4.37, for 50 μg 29.0 ± 7.08, for 300 μg 31.2 ± 6.68 and for 600 μg 32.7 ± 7.95) (P < 0.009), except 50 μg at 1 and 24 h. Significant decreases in Raw were observed with aclidinium 300 and 600 μg compared with placebo at all assessments (Raw mean ± SD AUC (kPa s-1 l-1 h) for placebo 7.7 ± 3.46, for 300 μg 5.8 ± 2.33, for 600 μg 6.3 ± 3.11) (P < 0.04) except 600 μg at 24 h. Differences between aclidinium 300 and 600 μg vs. placebo in PC35 doubling concentration were significant at all assessments (mean ± SD AUC (mg ml-1 h) for placebo 100.0 ± 30.27, for 50 μg 117.2 ± 33.33, for 300 μg 168.9 ± 28.66 and for 600 μg 179.1 ± 15.73 (P < 0.0001). For all endpoints, there was a significant difference between aclidinium 50 μg and the higher doses (P < 0.0001). Aclidinium was not detected in plasma and was well tolerated. CONCLUSION Aclidinium produced statistically significant and sustained bronchodilation over 24 h, suggesting long-acting efficacy and providing a rationale for future studies in patients with COPD. © 2010 The British Pharmacological Society.