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Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Inhaled Once-Daily Umeclidinium in Healthy Adults Deficient in CYP2D6 Activity: A Double-Blind, Randomized Clinical Trial

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Abstract

Background

Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.

Objective

The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.

Methods

This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100–1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.

Results

Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration–time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUCτ (ng·h/mL)] and the maximum plasma concentration [Cmax (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79–1.34) and 0.80 (0.59–1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae24) [ng] ratio was 1.01 (0.82–1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUCτ [ng·h/mL] and Cmax (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98–1.81) and 1.07 (0.76–1.51); the urine Ae24 (ng) ratio was 1.47 (1.15–1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.

Conclusion

Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations.

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Notes

  1. ELLIPTA™ is a trade mark of the GlaxoSmithKline group of companies.

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Acknowledgments

GlaxoSmithKline funded this study (GSK protocol number AC4110106; ClinicalTrials.gov registration number NCT00803673); contributed to the protocol development; conducted the study; collected data; and prepared, reviewed and approved the manuscript. GlaxoSmithKline was responsible for the study design, collection of data, analysis and interpretation of data, writing of the study report, and the decision to submit the manuscript for publication (see below for the individual author contributions). The clinical phase of this study was conducted by SGS Life Sciences Services, Antwerp, Belgium. The authors would like to thank members of the GlaxoSmithKline team for their contribution to the study conduct, including Dawn Webber for providing the statistical analysis. Medical writing and editorial support, which was funded by GlaxoSmithKline, was provided by Dr Kathryn White of Cathean Limited Medical Writing Consultancy and Dr Tara N. Miller of Gardiner-Caldwell Communications.

Author contributions

Participated in research design: Anthony Cahn, Rashmi Mehta, Andrew Preece, James Blowers, Alison Donald. Conducted experiments: not applicable. Contributed new reagents or analytic tools: not applicable. Performed data analysis: Alison Donald, Rashmi Mehta. Wrote or contributed to the writing of the manuscript: Anthony Cahn, Rashmi Mehta, Andrew Preece, James Blowers, Alison Donald.

Conflict of interest disclosures

This study was funded by GlaxoSmithKline. All authors are employees of and hold stock in GlaxoSmithKline.

Author information

Authors and Affiliations

  1. Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Anthony Cahn

  2. Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, USA

    Rashmi Mehta, James Blowers & Alison Donald

  3. Respiratory Medicines Development Centre, GlaxoSmithKline, Stockley Park, UK

    Andrew Preece

Authors
  1. Anthony Cahn
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  2. Rashmi Mehta
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  3. Andrew Preece
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  4. James Blowers
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  5. Alison Donald
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Corresponding author

Correspondence to Anthony Cahn.

Additional information

Trial registration: ClinicalTrials.gov identifier: NCT00803673; GSK protocol number AC4110106.

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Cahn, A., Mehta, R., Preece, A. et al. Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Inhaled Once-Daily Umeclidinium in Healthy Adults Deficient in CYP2D6 Activity: A Double-Blind, Randomized Clinical Trial. Clin Drug Investig 33, 653–664 (2013). https://doi.org/10.1007/s40261-013-0109-6

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