A randomized, crossover study to investigate the pharmacokinetics and safety of inhaled fluticasone furoate and umeclidinium, administered separately and in combination via dry powder inhaler in healthy adult volunteers.

INTRODUCTION: A combination of fluticasone furoate (FF) and umeclidinium (UMEC) has been considered for development for the treatment of asthma. The primary objectives were to investigate the plasma and urine pharmacokinetics (PK) of FF/UMEC in combination compared with FF and UMEC monotherapies. METHODS: This randomized, double-blind, three-period crossover, single-center study in healthy volunteers assessed the PK of FF 400 mcg and UMEC 500 mcg administered separately and in combination (four inhalations of FF/UMEC 100/125 mcg, FF 100 mcg, or UMEC 125 mcg) via dual-strip dry powder inhaler. Subjects were randomized based on codes generated using a validated computerized system (Randall, GlaxoSmithKline). RESULTS: Eighteen subjects were enrolled; 17 received all three scheduled doses of study medication. Plasma FF and UMEC concentrations peaked at 0.5 and 0.08 h post-dose, respectively, for FF/UMEC and the monotherapies. FF and UMEC co-administration resulted in slightly lower or similar systemic exposure for both drugs versus the monotherapies. In post hoc sensitivity analyses (performed because two subjects administered inhalations incorrectly), the ratio of adjusted geometric means (maximum plasma concentration and area under the curve) was closer to unity than in the planned analyses. Cumulative urinary UMEC excretion (Ae) was similar for FF/UMEC and UMEC. Post hoc sensitivity analyses on Ae(0-24) suggested a small carryover effect but results were similar to those of the population as a whole. Urinary UMEC excretion following FF/UMEC was low (~1.5% over 24 h) and unlikely to have impacted upon PK comparisons. Three adverse events were reported; none were severe or led to withdrawal. There were no clinically significant effects on electrocardiogram, vital sign, or laboratory parameters. CONCLUSION: Fluticasone furoate and umeclidinium co-administration was well tolerated and was not associated with meaningful changes in systemic or urinary PK versus the monotherapies. FUNDING: GlaxoSmithKline.

Combined fluticasone furoate/vilanterol reduces decline in lung function following inhaled allergen 23 h after dosing in adult asthma: a randomised, controlled trial.

BACKGROUND: There is a need for preventative asthma maintenance therapy that provides lasting bronchoprotection against allergen provocation. Fluticasone furoate (FF) is a novel inhaled once-daily corticosteroid, being investigated as monotherapy for asthma and in combination with vilanterol (VI), a novel inhaled once-daily long-acting beta-agonist, for asthma and chronic obstructive pulmonary disease. METHODS: In a crossover study of 52 subjects with mild asthma, FF/VI 100/25mcg and FF 100 dosed once-daily in the evening for 28 days were compared with placebo to evaluate their capacity to provide bronchoprotection against the early asthmatic response (EAR) stimulated by an inhaled allergen challenge. Bronchoprotection was assessed by change from post-saline baseline in weighted mean (wm) forced expiratory volume in 1 s (FEV1) for the first 2 h post-allergen challenge, which was on Day 29 (22-23 h post final dose on Day 28). The EAR was also assessed using maximum percent decrease from post-saline baseline and minimum absolute FEV1; the incidence of adverse events was a secondary endpoint. RESULTS: FF/VI 100/25 and FF 100 both provided significant bronchoprotection against the EAR for all endpoints assessed. For wmFEV1 over the first 2 h post-allergen challenge, a 162 mL (95% CI, 87 to 237 mL) difference was observed between placebo and FF 100, while a 145 mL (95% CI, 69 to 222 mL) difference was observed between placebo and FF/VI 100/25 treatment. No difference between active treatments was observed (-17 mL; 95% CI, -91 to 57 mL). Both treatments were well tolerated. CONCLUSIONS: FF 100 alone and in combination with VI 25 provides significant bronchoprotection against the EAR in subjects with mild asthma. That this protection is provided at the trough of dosing, i.e. 23 h post last dose, supports the utility of FF 100 and FF/VI 100/25 as viable once-daily therapies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01128569, GSK Study number: HZA113090.