PMID- 23881566
OWN - NLM
STAT- MEDLINE
DCOM- 20140424
LR  - 20211021
IS  - 1179-1918 (Electronic)
IS  - 1173-2563 (Linking)
VI  - 33
IP  - 9
DP  - 2013 Sep
TI  - Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled 
      once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a 
      double-blind, randomized clinical trial.
PG  - 653-64
LID - 10.1007/s40261-013-0109-6 [doi]
AB  - 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 mug) 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(tau) (ng.h/mL)] and the maximum plasma concentration [C(max) 
      (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing 
      with 500 mug 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 mug, the plasma 
      AUC(tau) [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. CONCLUSION: Umeclidinium has favourable safety and pharmacokinetic 
      profiles in both HVT-NM and HVT-PM populations.
FAU - Cahn, Anthony
AU  - Cahn A
AD  - Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 
      2NY, UK. tony.x.cahn@gsk.com
FAU - Mehta, Rashmi
AU  - Mehta R
FAU - Preece, Andrew
AU  - Preece A
FAU - Blowers, James
AU  - Blowers J
FAU - Donald, Alison
AU  - Donald A
LA  - eng
SI  - ClinicalTrials.gov/NCT00803673
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - New Zealand
TA  - Clin Drug Investig
JT  - Clinical drug investigation
JID - 9504817
RN  - 0 (GSK573719)
RN  - 0 (Muscarinic Antagonists)
RN  - 0 (Quinuclidines)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
SB  - IM
MH  - Administration, Inhalation
MH  - Adolescent
MH  - Adult
MH  - Cytochrome P-450 CYP2D6/*deficiency/physiology
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Humans
MH  - Middle Aged
MH  - Muscarinic Antagonists/*adverse effects
MH  - Quinuclidines/administration & dosage/*adverse effects/pharmacokinetics
EDAT- 2013/07/25 06:00
MHDA- 2014/04/25 06:00
CRDT- 2013/07/25 06:00
PHST- 2013/07/25 06:00 [entrez]
PHST- 2013/07/25 06:00 [pubmed]
PHST- 2014/04/25 06:00 [medline]
AID - 10.1007/s40261-013-0109-6 [doi]
PST - ppublish
SO  - Clin Drug Investig. 2013 Sep;33(9):653-64. doi: 10.1007/s40261-013-0109-6.