title: Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind, randomized clinical trial.
abstract: BACKGROUND
  Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.
  
  
  OBJECTIVE
  The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.
  
  
  METHODS
  This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.
  
  
  RESULTS
  Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUC(τ) (ng·h/mL)] and the maximum plasma concentration [C(max) (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae(24)) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUC(τ) [ng·h/mL] and C(max) (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae(24) (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.
  
  
  CONCLUSIONS
  Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations.
authors.affiliation: Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. tony.x.cahn@gsk.com
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: James
authors.initials: J
authors.lastname: Blowers
authors.forename: Alison
authors.initials: A
authors.lastname: Donald
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D019389:Cytochrome P-450 CYP2D6 / Q000172:deficiency* / Q000502:physiology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects*; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D019389:Cytochrome P-450 CYP2D6