Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease

Clin Pharmacokinet. 2020 Jan;59(1):67-79. doi: 10.1007/s40262-019-00794-w.


Background: Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler.

Methods: Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM®.

Results: The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/F) with FF CL/F 35% lower in patients of Japanese heritage across all treatments and FF CL/F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/F and weight on apparent volume of distribution (V2/F) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/F and approximately an 8% increase in UMEC V2/F. For a subject with COPD who smoked, UMEC CL/F was 28% higher. For VI, weight on CL/F and smoking status on V2/F with an approximately 4% increase in VI CL/F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment.

Conclusions: All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Trial registration: ClinicalTrials.gov NCT02729051 NCT02345161 NCT02164513.

Keywords: COPD; Fluticasone furoate; Population pharmacokinetics; Umeclidinium; Vilanterol.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Aged
  • Androstadienes / administration & dosage
  • Androstadienes / blood
  • Androstadienes / pharmacokinetics*
  • Androstadienes / therapeutic use
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / blood
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / therapeutic use
  • Benzyl Alcohols / administration & dosage
  • Benzyl Alcohols / blood
  • Benzyl Alcohols / pharmacokinetics*
  • Benzyl Alcohols / therapeutic use
  • Bromides / administration & dosage
  • Bromides / blood
  • Bromides / pharmacokinetics*
  • Bromides / therapeutic use
  • Chlorobenzenes / administration & dosage
  • Chlorobenzenes / blood
  • Chlorobenzenes / pharmacokinetics*
  • Chlorobenzenes / therapeutic use
  • Drug Combinations
  • Female
  • Humans
  • Male
  • Middle Aged
  • Muscarinic Antagonists / administration & dosage
  • Muscarinic Antagonists / blood
  • Muscarinic Antagonists / pharmacokinetics
  • Muscarinic Antagonists / therapeutic use
  • Predictive Value of Tests
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / ethnology
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Quinuclidines / administration & dosage
  • Quinuclidines / blood
  • Quinuclidines / pharmacokinetics*
  • Quinuclidines / therapeutic use


  • Androstadienes
  • Anticonvulsants
  • Benzyl Alcohols
  • Bromides
  • Chlorobenzenes
  • Drug Combinations
  • GSK573719
  • Muscarinic Antagonists
  • Quinuclidines
  • vilanterol
  • fluticasone furoate

Associated data

  • ClinicalTrials.gov/NCT02729051
  • ClinicalTrials.gov/NCT02345161
  • ClinicalTrials.gov/NCT02164513