title: Tolerability of fluticasone furoate/vilanterol combination therapy in children aged 5 to 11 years with persistent asthma.
abstract: BACKGROUND
  Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β2-agonist.
  
  
  OBJECTIVE
  We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β2-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma.
  
  
  METHODS
  In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0-4 hours]) parameters on day 14.
  
  
  RESULTS
  Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study.
  
  
  CONCLUSIONS
  Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.
authors.affiliation: GlaxoSmithKline, Uxbridge, United Kingdom. Electronic address: Amanda.j.oliver@gsk.com.
authors.forename: Amanda
authors.initials: A
authors.lastname: Oliver
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Sandi
authors.initials: S
authors.lastname: VanBuren
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Ann
authors.initials: A
authors.lastname: Allen
authors.affiliation: GlaxoSmithKline, Ware, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hamilton
authors.affiliation: Synergy, Slough, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Tombs
authors.affiliation: GlaxoSmithKline, Uxbridge, United Kingdom.
authors.forename: Amir
authors.initials: A
authors.lastname: Inamdar
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Rodger
authors.initials: R
authors.lastname: Kempsford
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000730:Androstadienes / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D001592:Benzyl Alcohols / Q000008:administration & dosage*; D002648:Child; D002722:Chlorobenzenes / Q000008:administration & dosage*; D002908:Chronic Disease; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D058995:Dry Powder Inhalers; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D008297:Male; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000730:Androstadienes; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D004338:Drug Combinations; D005938:Glucocorticoids; C550468:vilanterol; C523187:fluticasone furoate
keywords: ICS; LABA; pediatric; pharmacodynamics; pharmacokinetics; tolerability