Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Inhaled Doses of Umeclidinium in Healthy Subjects: Two Randomized Studies

Abstract

Chronic obstructive pulmonary disease (COPD) has a significant negative impact on quality of life and increases the risk of premature death. Umeclidinium is a long-acting muscarinic receptor antagonist in development for the treatment of COPD with the aim to broaden treatment options for clinicians and patients by providing improved symptom control. To characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects. Two randomized, placebo-controlled, ascending-dose studies were conducted in healthy ipratropium bromide-responsive subjects. In the single-dose study, subjects (n=20) received umeclidinium (10-350μg), tiotropium bromide 18μg and placebo in a crossover dosing schedule. In this study, lung function was assessed for 24h by measuring specific airways conductance (sGaw) and forced expiratory volume in 1s (FEV1). In the repeat-dose study, subjects (n=36) received umeclidinium (250-1,000μg) and placebo for 14days in a parallel-group schedule. Adverse events (AEs) were reported in five subjects (single-dose study) and 23subjects (repeat-dose study); none were serious. In both studies, no abnormalities in 12-lead electrocardiogram parameters, 24-h Holter monitoring or lead II monitoring were reported as AEs. Umeclidinium was rapidly absorbed following single-dose administration [time to reach the maximum plasma concentration (tmax) 5-15min] and repeat-dose administration (tmax 5-7min). Following repeat dosing, the geometric mean plasma elimination half-life was approximately 27h and statistically significant accumulation was observed for the area under the plasma concentration-time curve, maximum plasma concentration and cumulative amount of unchanged drug excreted into the urine at 24h (range 1.5- to 4.5-fold). Umeclidinium at doses of 100μg and above, and tiotropium bromide demonstrated statistically significant bronchodilatory effects relative to placebo at 12h post-dosing, which lasted up to 24h for umeclidinium 350μg and for tiotropium bromide. Relative to placebo, these increases in sGaw were 24-34% at 12h post-dose and 13% at 24h post-dose. Increases in FEV1 achieved statistical significance at 12 and 24h for umeclidinium 100μg and 350μg compared with placebo. Umeclidinium was well tolerated and demonstrated bronchodilatory effects in healthy subjects for up to 24h. These bronchodilatory effects can be potentially clinically important in patients with airway obstruction such as COPD. The data obtained have informed dose selection for subsequent trials in subjects with COPD.