title: Dose-response modelling of umeclidinium and fluticasone furoate/umeclidinium in asthma.
abstract: OBJECTIVE
  In two dose-ranging crossover studies, the long-acting muscarinic antagonist umeclidinium (UMEC) was assessed as monotherapy in patients with asthma not treated with inhaled corticosteroids (ICS) (NCT01641692 [study 1]) and combined with the ICS fluticasone furoate (FF) in patients with asthma symptomatic on ICS (NCT01573624 [study 2]). The present study aimed to further characterise the UMEC dose-response relationship with change from baseline trough forced expiratory volume in one second (FEV1) (day 15).
  
  
  METHODS
  A model-based approach using non-linear mixed-effects analyses was used to assess data from studies 1 and 2.
  
  
  RESULTS
  Within the Study 1 dose range, no significant dose-response was demonstrated. In study 2, the slope-intercept on log-dose model showed a mild dose-response, with a 10 % probability of a 0.075-L FEV1 improvement with FF/UMEC 100/250 mcg; period 1 data (with an absent carryover effect) indicated an 88 % probability of a 0.075-L FEV1 improvement.
  
  
  CONCLUSIONS
  The model-based approach in study 2 identified FF/UMEC doses warranting further investigation.
authors.affiliation: Clinical Pharmacology, Modelling and Simulation, R&D Projects Clinical Platforms and Sciences, GlaxoSmithKline, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, Middlesex, UB11 1BT, UK, shuying.y.yang@gsk.com.
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
authors.forename: Navin
authors.initials: N
authors.lastname: Goyal
authors.forename: Misba
authors.initials: M
authors.lastname: Beerahee
authors.forename: Roopa
authors.initials: R
authors.lastname: Trivedi
authors.forename: Laurie
authors.initials: L
authors.lastname: Lee
authors.forename: Steven
authors.initials: S
authors.lastname: Pascoe
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use; D000730:Androstadienes / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D017711:Nonlinear Dynamics; D011812:Quinuclidines / Q000627:therapeutic use*
chemical_list: D000305:Adrenal Cortex Hormones; D000730:Androstadienes; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C523187:fluticasone furoate