title: Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies.
abstract: 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 (250μg, 500μg, and 1000μg), tiotropium bromide 18μg 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 (250μg and 1000μg) 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 24h for all active treatments compared with placebo. Increases in forced expiratory volume in 1s were also observed. Pharmacokinetic analysis demonstrated that maximum observed plasma umeclidinium concentration (Cmax) was reached rapidly (time to Cmax: ∼5-15min) 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 24h in patients with COPD.
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.forename: Anthony
authors.initials: A
authors.lastname: Cahn
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.forename: Andrew
authors.initials: A
authors.lastname: Preece
authors.forename: Glenn
authors.initials: G
authors.lastname: Crater
authors.forename: Dennis
authors.initials: D
authors.lastname: Kelleher
authors.forename: Isabelle J
authors.initials: IJ
authors.lastname: Pouliquen
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D004334:Drug Administration Schedule; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011812:Quinuclidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012449:Safety
chemical_list: C573971:GSK573719; D011812:Quinuclidines