Safety, tolerability and pharmacokinetics of single escalating doses of indacaterol, a once-daily β2-agonist bronchodilator, in subjects with COPD

Objectives: To assess the safety and tolerability of 4 doses of indacaterol, a once-daily beta(2)-agonist, in subjects with chronic obstructive pulmonary disease (COPD). The 24-h bronchodilator effect and pharmacokinetics of indacaterol were also investigated. Methods: 16 subjects aged 43 72 years with mild/moderate COPD were each given single doses of indacaterol of 400, 1,000, 2,000 and 3,000 mu g, via a single-dose dry powder inhaler. Results: Changes from predose (400, 1,000, 2,000, 3,000 mu g doses, respectively) were as follows. Maximum mean decreases in fasting (up to 2 h post-dose) serum potassium were 0.12, 0.30, 0.38, 0.26 mmol/l; maximum mean increases (up to 2 h post-dose) in fasting serum glucose were 0.12, 0.40, 0.87, 1.01 mmol/l. The maximum increase in heart rate (by 3, 6, 12, 13 beats/min, respectively) was within 1 h post-dose. No clinically significant electrocardiogram abnormalities were reported. Most adverse events were mild or moderate, with none considered serious or leading to withdrawal. Indacaterol was rapidly absorbed and displayed multiphasic disposition kinetics. The terminal elimination phase with a half-life of 50 63 h could only be seen for doses of 1,000 mu g or higher. Mean systemic exposure to indacaterol (AUC(0-24)) increased by similar to 9-fold from 400 to 3,000 mu g. Conclusion: Even at doses far in excess of the therapeutic range, indacaterol had minimal systemic effects; such changes would be considered within safe limits for a single dose.