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

Figure 1

Mean (± SE) changes in specific airway conductance (sGaw, %) over 24 h as a percentage of baseline value. Placebo (); 50 µg aclidinium bromide (); 300 µg aclidinium bromide (); 600 µg aclidinium bromide ()

Figure 2

Mean (± SE) changes in airway resistance (Raw, %) over 24 h as a percentage of baseline value. Placebo (); 50 µg aclidinium bromide (); 300 µg aclidinium bromide (); 600 µg aclidinium bromide ()

Figure 3

Effect of aclidinium on methacholine-induced bronchoconstriction, as measured by PC35 sGaw doubling concentrations (data shown as least squares means ± SE). Placebo (); 50 µg aclidinium bromide (); 300 µg aclidinium bromide (); 600 µg aclidinium bromide ()