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.

Abstract

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. 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). 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. Fluticasone furoate and umeclidinium co-administration was well tolerated and was not associated with meaningful changes in systemic or urinary PK versus the monotherapies. GlaxoSmithKline.