title: Population Pharmacokinetics Modeling of Inhaled Umeclidinium for Adult Patients with Asthma.
abstract: BACKGROUND
  Umeclidinium (UMEC; a long-acting anti-muscarinic) in combination with fluticasone furoate (an inhaled corticosteroid) is in development for asthma treatment. This secondary analysis aimed to develop a population pharmacokinetic model characterizing UMEC in adults with asthma, and evaluated the impact of covariates on pharmacokinetic parameters.
  
  
  METHODS
  Plasma concentration data from study NCT01641692 (assessing once-daily UMEC 15.6, 31.25, 62.5, 125, and 250 mcg, twice daily UMEC 15.6 and 31.25 mcg, and placebo) were analyzed using non-linear mixed-effect modeling in NONMEM®. Full likelihood, including observed data and data below the quantification limit (treated as censored), was maximized. Study endpoints were population pharmacokinetics (including apparent inhaled clearance [CL/F] and apparent distribution volume in the central compartment [Vc/F]) and derived pharmacokinetic parameters (area under the concentration-time curve [AUC] and maximum concentration [Cmax] at steady-state).
  
  
  RESULTS
  In total, 128 patients provided 3757 data points. The pharmacokinetics of UMEC were best described using a two-compartment model with intravenous bolus input, due to fast absorption following inhalation. CL/F was 257 L/h and Vc/F was 804 L. Creatinine clearance was a significant covariate for CL/F, as were age and body weight for Vc/F. AUC and Cmaxincreased with increasing UMEC dose (once-daily 15.6-250 mcg: AUC0-24median: 64.7-863 pg h/mL; Cmaxmedian: 10.6-256 pg/mL).
  
  
  CONCLUSIONS
  The final population pharmacokinetic model adequately described the data, demonstrating minimal creatinine clearance, age, and body weight effects on overall plasma UMEC pharmacokinetics and systemic exposure.
authors.affiliation: GSK, Respiratory Medicines Development Centre, Stockley Park, Middlesex, UK. shuying.y.yang@gsk.com.|Clinical Pharmacology, Modelling and Simulation, R&D Projects Clinical Platforms and Sciences, GSK, Stockley Park West, 1-3 Iron Bridge Road, Uxbridge, Middlesex, UB11 1BT, UK. shuying.y.yang@gsk.com.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
authors.affiliation: GSK, Respiratory Medicines Development Centre, Stevenage, UK.
authors.forename: Laurie
authors.initials: L
authors.lastname: Lee
authors.affiliation: GSK, Respiratory Medicines Development Center, Research Triangle Park, NC, 27709-3398, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Pascoe
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D001249:Asthma / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011812:Quinuclidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: C573971:GSK573719; D011812:Quinuclidines