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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

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Abstract

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 Ae0–24 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.

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Acknowledgments

Afia Akram, PhD, and Natasha Thomas, PhD, of Fishawack Indicia Ltd, provided editorial and formatting assistance in the preparation of the manuscript, which was funded by GlaxoSmithKline. GlaxoSmithKline funded this study, and was involved in the study design, the conduct of the study and the collection, analysis and interpretation of data. The associated article processing charges were funded by GlaxoSmithKline. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Conflict of interest

Shuying Yang is an employee of GlaxoSmithKline and holds GlaxoSmithKline stock options. Laurie Lee is an employee of GlaxoSmithKline and holds GlaxoSmithKline stock options. Stephen Mallett is an employee of GlaxoSmithKline and holds GlaxoSmithKline stock options. Jonathan Ayer is an employee of GlaxoSmithKline and holds GlaxoSmithKline stock options. Allen Wolstenholme is an employee of GlaxoSmithKline and holds GlaxoSmithKline stock options. Steven Pascoe is an employee of GlaxoSmithKline and holds GlaxoSmithKline stock options.

Compliance with ethics guidelines

This study was approved by an appropriate ethics committee, and was therefore performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All subjects gave their informed consent prior to their inclusion in the study.

Author information

Authors and Affiliations

  1. GlaxoSmithKline, Uxbridge, Middlesex, UK

    Shuying Yang, Stephen Mallett & Jonathan Ayer

  2. GlaxoSmithKline, Research Triangle Park, NC, USA

    Laurie Lee & Steven Pascoe

  3. GlaxoSmithKline, King of Prussia, PA, USA

    Allen Wolstenholme

Authors
  1. Shuying Yang
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  2. Laurie Lee
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  3. Stephen Mallett
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  4. Jonathan Ayer
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Corresponding author

Correspondence to Shuying Yang.

Additional information

Trial registration: ClinicalTrials.gov #NCT01725685.

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Yang, S., Lee, L., Mallett, S. et al. 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. Adv Ther 32, 157–171 (2015). https://doi.org/10.1007/s12325-015-0184-6

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