Pulmonary, gastrointestinal and urogenital pharmacologyInitial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: Two randomised studies

To characterise the safety, tolerability, pharmacodynamics (bronchodilatory effect) and pharmacokinetics of inhaled umeclidinium in patients with chronic obstructive pulmonary disease (COPD).The first investigation was a single dose, randomised, double-blind, placebo-controlled study (clinicaltrials.gov: NCT00515502) in which ipratropium bromide-sensitive patients received umeclidinium (250 μg, 500 μg, and 1000 μg), tiotropium bromide 18 μg or placebo. Patients were randomised to receive four out of five possible treatments as an incomplete block four-way cross-over. A subsequent study (clinicaltrials.gov: NCT700732472) was focused on assessment of safety, tolerability and pharmacokinetics of umeclidinium (250 μg and 1000 μg) administered once-daily for 7 days in a randomised, double-blind, placebo-controlled, parallel-group design.Of the 24 patients randomised for the single dose study, 20 completed; 31 out of 38 patients completed the repeat dose study. Most adverse events were mild-to-moderate and transient. Examination of heart rate, QTc interval, blood pressure and clinical laboratory assessments raised no concern over the safety of umeclidinium. Evidence of pharmacology was demonstrated in first study by statistically significant increases in specific airway conductance (sGaw) for up to 24 h for all active treatments compared with placebo. Increases in forced expiratory volume in 1 s were also observed. Pharmacokinetic analysis demonstrated that maximum observed plasma umeclidinium concentration (Cmax) was reached rapidly (time to Cmax: ∼5-15 min) after single and repeat doses; 1.5-1.9-fold accumulation was observed after repeat-dosing.Single and repeat doses of umeclidinium were well tolerated and produced clinically relevant lung function improvements over 24 h in patients with COPD.