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Concentration-QT analysis of the randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects

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Abstract

The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once-daily monotherapy and in combination with the long-acting β2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia’s correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1–10: n = 77 subjects received placebo, n = 76 UMEC 500 µg, n = 78 UMEC/VI 125/25 µg, or n = 76 UMEC/VI 500/100 µg; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed-effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was −2.38 ms (90 % prediction interval [PI] −3.82, −0.85) with UMEC 500 µg and −0.50 ms (90 % PI −0.80, −0.18) and −2.01 ms (90 % PI −3.22, −0.72) with UMEC/VI 125/25 µg and 500/100 µg, respectively. For VI, estimates were 5.89 ms (90 % PI 4.89, 6.91) and 7.23 ms (90 % PI 5.88, 8.55) with UMEC/VI 125/25 µg and 500/100 µg, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25 µg (5.39 ms [90 % PI 4.40, 6.47]) and 500/100 µg (5.22 ms [90 % PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses.

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Acknowledgments

Editorial support in the form of development of a draft outline in consultation with the authors, development of a manuscript first draft in consultation with the authors, editorial suggestions to draft versions of this paper, assembling tables and collating author comments, copyediting, fact checking, and referencing was provided by Tara N Miller, PhD (employed by Gardiner-Caldwell Communications, Lyndhurst, NJ, USA, until November 2013) and by Laura Maguire, MChem, at Gardiner-Caldwell Communications (Gardiner-Caldwell Communications, Macclesfield, UK) and was funded by GSK. Editorial support in the form of styling the manuscript to comply with journal guidelines was provided by James Andrews, BA, of Fishawack Indicia Ltd and then in the form of peer-review comment incorporation by Joanne Ashworth, BSc, also of Fishawack Indicia Ltd and was also funded by GSK.

Funding

The study was sponsored by GSK. Employees of the sponsor were involved in the conception, design and conduct of the study, and in data collection and analysis.

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Author notes

  1. Jonathan Wagg

    Present address: Clinical Pharmacology, Head Oncology Modeling, Roche, Basel, Switzerland

Authors and Affiliations

  1. Clinical Pharmacology Modeling Simulation, GSK, 5 Moore Drive, Research Triangle Park, NC, 27709, USA

    Rashmi Mehta

  2. Quantitative Solutions, Menlo Park, CA, USA

    Michelle Green

  3. Clinical Pharmacology Modeling Simulation, GSK, King of Prussia, Philadelphia, PA, USA

    Bela Patel

  4. Translational Medicine, Shire, Eysins, Switzerland

    Jonathan Wagg

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Correspondence to Rashmi Mehta.

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Conflicts of interest

RM and BP are employees of, and hold stock in, GSK. MG and JW were former employees of Pharsight, a contract research organization, which was contracted by GSK to perform the analyses presented in this manuscript; they did not receive any financial support for their involvement in development of the manuscript.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Mehta, R., Green, M., Patel, B. et al. Concentration-QT analysis of the randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. J Pharmacokinet Pharmacodyn 43, 153–164 (2016). https://doi.org/10.1007/s10928-015-9461-x

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