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

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 mu g) 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 mu g 29.0 +/- 7.08, for 300 mu g 31.2 +/- 6.68 and for 600 mu g 32.7 +/- 7.95) (P < 0.009), except 50 mu g at 1 and 24 h. Significant decreases in Raw were observed with aclidinium 300 and 600 mu g compared with placebo at all assessments (Raw mean SD AUC (kPa s(-1) l(-1) h) for placebo 7.7 +/- 3.46, for 300 mu g 5.8 +/- 2.33, for 600 mu g 6.3 +/- 3.11) (P < 0.04) except 600 mu g at 24 h. Differences between aclidinium 300 and 600 mu g 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 mu g 117.2 +/- 33.33, for 300 mu g 168.9 +/- 28.66 and for 600 mu g 179.1 +/- 15.73 (P < 0.0001). For all endpoints, there was a significant difference between aclidinium 50 mu g 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