title: Pharmacokinetics and pharmacodynamics of GSK961081, a novel inhaled muscarinic antagonist β2 -agonist, and fluticasone propionate administered alone, concurrently and as a combination blend formulation in healthy volunteers.
abstract: To investigate the pharmacokinetics and pharmacodynamics of inhaled GSK961081 and fluticasone propionate (FP) given alone, concurrently and as a combination blend formulation.
  
  
  
  The study was double-blind, double-dummy, four-way crossover. Twenty-four healthy volunteers took single doses of the following in randomized order: (1) GSK961081 800 µg; (2) FP 500 µg; (3) GSK961081 800 µg and FP 500 µg as a blend formulation; and (4) GSK961081 800 µg and FP 500 µg concurrently via separate inhalers. The eLung breathing simulator was also used for the in vitro characterization of the formulations.
  
  
  
  There was no pharmacokinetic interaction when GSK961081 and FP were administered concurrently. Mean Cmax and AUC(0-t) of GSK961081 were lower (∼20%) and mean Cmax and AUC(0-t) of FP were higher (two fold) following GSK961081/FP blend formulation compared to concurrent or the individual components alone. There was an increase in the FP in vitro ex-throat dose for the GSK961081/FP blend from the eLung breathing simulator. Serum cortisol suppression was greater with GSK961081/FP blend, with lower (∼10%) cortisol levels than after GSK961081 + FP concurrent or FP alone.
  
  
  
  GSK961081/FP blend formulation was associated with an increase in FP systemic exposure and greater serum cortisol suppression.
authors.affiliation: GlaxoSmithKline, UK.
authors.forename: Virginia
authors.initials: V
authors.lastname: Norris
authors.affiliation: GlaxoSmithKline, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Ambery
authors.affiliation: GlaxoSmithKline, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Riley
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D004339:Drug Compounding; D004359:Drug Therapy, Combination; D058995:Dry Powder Inhalers; D005260:Female; D000068298:Fluticasone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D015415:Biomarkers; D002219:Carbamates; D004338:Drug Combinations; D018727:Muscarinic Antagonists; D015363:Quinolones; C588122:batefenterol; D000068298:Fluticasone; D006854:Hydrocortisone
keywords: GSK961081; bi-functional molecule; bronchodilator; fluticasone propionate; muscarinic receptor antagonist and β2-adrenoreceptor agonist