title: Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease.
abstract: OBJECTIVE
  A fixed-dose combination of the bronchodilators umeclidinium and vilanterol is in development for the long-term, once-daily treatment of chronic obstructive pulmonary disease (COPD). We characterized the pharmacokinetics of umeclidinium and vilanterol in ≈1,635 patients with COPD, evaluating the impact of patient demographics and baseline characteristics on umeclidinium and vilanterol exposure.
  
  
  METHODS
  Plasma concentrations of umeclidinium and vilanterol were evaluated in patients enrolled in two phase III, randomized, double-blind, parallel-group, placebo-controlled trials using inhaled umeclidinium/vilanterol combination therapy and inhaled umeclidinium and vilanterol monotherapies as treatments. Population-pharmacokinetic models were developed using non-linear mixed-effects analyses, performed using NONMEM(®) software. A likelihood-based approach was used to characterize the data below limit of quantification. Umeclidinium and vilanterol exposures at clinical doses were simulated based on the population model.
  
  
  RESULTS
  For the umeclidinium and vilanterol population-pharmacokinetic analyses, 1,635 and 1,637 patients provided 8,498 and 8,405 observations, respectively. Umeclidinium and vilanterol pharmacokinetics were best described by a two-compartment model with first-order absorption. For umeclidinium, bodyweight, age, and creatinine clearance (CLCR) were statistically significant covariates for apparent inhaled clearance (CL/F); bodyweight was a statistically significant covariate for volume of distribution of central compartment (V 2/F).The population parameter estimates namely CL/F and V 2/F for umeclidinium were 218 L/h and 1,160 L and 40.9 L/h and 268 L for vilanterol. For vilanterol, bodyweight and age were statistically significant covariates for CL/F. The effect of covariates on umeclidinium and vilanterol systemic exposure was marginal. The population model indicates that a 10 % increase in bodyweight will result in a 2 % increase in CL/F for umeclidinium and vilanterol and 6 % increase in umeclidinium V 2/F. A 10 % increase in age will provide a 7 and 4 % decrease in umeclidinium and vilanterol CL/F, respectively. A 10 % decrease in CLCR will result in a 3 % decrease in umeclidinium CL/F. Umeclidinium and vilanterol population-pharmacokinetic model-based systemic exposure predictions showed no pharmacokinetic interactions between umeclidinium and vilanterol when administered in combination.
  
  
  CONCLUSIONS
  There were no apparent pharmacokinetic interactions when umeclidinium and vilanterol were co-administered in patients with COPD. The effects of patient demographics, including age, bodyweight, and CLCR, on umeclidinium or vilanterol systemic exposure were minimal, and therefore no dose adjustments are necessary.
authors.affiliation: GlaxoSmithKline Research and Development, Pharmacokinetics, 709 Swedeland Road, UW2431, King of Prussia, PA, 19406, USA, navingoyal@gmail.com.
authors.forename: Navin
authors.initials: N
authors.lastname: Goyal
authors.forename: Misba
authors.initials: M
authors.lastname: Beerahee
authors.forename: Chris
authors.initials: C
authors.lastname: Kalberg
authors.forename: Alison
authors.initials: A
authors.lastname: Church
authors.forename: Sally
authors.initials: S
authors.lastname: Kilbride
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001592:Benzyl Alcohols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002722:Chlorobenzenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017326:Clinical Trials, Phase III as Topic; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011812:Quinuclidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C550468:vilanterol
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