Open-Label, Crossover Study to Determine the Pharmacokinetics of Fluticasone Furoate and Batefenterol When Administered Alone, in Combination, or Concurrently

Claire Ambery, Graeme Young, Teresa Fuller, Alex Georgiou, David Ramsay, Adeep Puri, Peter Daley-Yates, Claire Ambery, Graeme Young, Teresa Fuller, Alex Georgiou, David Ramsay, Adeep Puri, Peter Daley-Yates

Abstract

The study aim was to investigate the pharmacokinetics of single high doses and repeated therapeutic doses of fluticasone furoate (FF) and batefenterol (BAT; a bifunctional muscarinic antagonist and β2 -agonist) administered in combination (BAT/FF) or as monotherapy. In this open-label, 6-period, crossover study of 48 subjects, the treatment sequences were (1) single high-dose BAT/FF 900/300 μg followed by repeated therapeutic doses of BAT/FF 300/100 μg (once daily for 7 days); (2) single high-dose BAT 900 μg administered concurrently with FF 300 μg; (3) single high-dose BAT 900 μg followed by repeated therapeutic-dose BAT 300 μg; (4) single high-dose FF 300 μg followed by repeated therapeutic-dose FF 100 μg; (5) single high-dose FF 300 μg (magnesium stearate); and (6) single high-dose FF/vilanterol 300/75 μg. Plasma FF area under the plasma drug concentration-time curve (AUC) was reduced after single high-dose BAT/FF versus FF alone (ratio of geometric least squares means: 0.79; 90% confidence interval: 0.75-0.83). After repeat dosing, FF AUC at the lower therapeutic dosage was similar for BAT/FF and FF (primary endpoint; AUC geometric least squares means: 1.03). Adverse events were minor, the most common being cough. These data support the feasibility of developing BAT/inhaled corticosteroid triple therapy in a single inhaler.

Trial registration: ClinicalTrials.gov NCT02666287.

Keywords: batefenterol; bifunctional molecule; bronchodilator; fluticasone furoate; triple therapy.

Conflict of interest statement

C.A., G.Y., T.F., A.G., and P.D‐Y. are employees of GSK and hold stocks or shares in the company. A.P.’s employer (Hammersmith Medicines Research Ltd) has received funding from GSK for studies outside of this submitted work. D.R.’s employer (Quanticate) supported the analysis and reporting of the current study.

© 2018, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean plasma FF concentration‐time plots, by treatment regimen following A) single high doses (day 1; PK population) and B) repeat dosing at therapeutic dose (day 8; PK population). BAT, batefenterol; FF, fluticasone furoate; MgSt, magnesium stearate; PK, pharmacokinetic; RD, repeated‐dose regimen; SD, single‐dose regimen. The dashed horizontal lines refer to the LLQ for each assessment. All plotted data points represent the arithmetic mean. All values below the limit of quantification were added as zero and included within the calculation of means. Error bars represent standard error.
Figure 2
Figure 2
Mean plasma BAT concentration‐time plots, by treatment regimen, following (A) single high doses (day 1; PK population) and (B) repeat dosing at anticipated therapeutic doses (day 8; PK population). BAT, batefenterol; FF, fluticasone furoate; MgSt, magnesium stearate; PK, pharmacokinetic; RD, repeated‐dose regimen; SD, single‐dose regimen. The dashed horizontal lines refer to the LLQ for each assessment. All plotted data points represent the arithmetic mean. All values below the limit of quantification were added as zero and included within the calculation of means. Error bars represent standard error.

References

    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) . Global Strategy for the Diagnosis, Management and Prevention of COPD. Accessed July 14, 2017.
    1. Cazzola M, Molimard M. The scientific rationale for combining long‐acting beta2‐agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23(4):257–267.
    1. Kerwin EM, Kalberg CJ, Galkin DV, et al. Umeclidinium/vilanterol as step‐up therapy from tiotropium in patients with moderate COPD: a randomized, parallel‐group, 12‐week study. Int J Chron Obstruct Pulmon Dis. 2017;12:745–755.
    1. Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) versus its monocomponents and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(9):1068–1079.
    1. Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2(6):472–486.
    1. Donohue JF, Maleki‐Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once‐daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107(10):1538–1546.
    1. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long‐acting beta(2)‐agonist in one inhaler versus long‐acting beta(2)‐agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012(9):Cd006829.
    1. Nannini LJ, Poole P, Milan SJ, Kesterton A. Combined corticosteroid and long‐acting beta(2)‐agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013(8):Cd006826.
    1. Montuschi P, Malerba M, Macis G, Mores N, Santini G. Triple inhaled therapy for chronic obstructive pulmonary disease. Drug Discov Today. 2016;21(11):1820–1827.
    1. Hughes AD, Chen Y, Hegde SS, et al. Discovery of (R)‐1‐(3‐((2‐chloro‐4‐(((2‐hydroxy‐2‐(8‐hydroxy‐2‐oxo‐1,2‐dihydroquinolin‐5‐yl)et hyl)amino)methyl)‐5‐methoxyphenyl)amino)‐3‐oxopropyl)piperidin‐4‐yl [1,1′‐biphenyl]‐2‐ylcarbamate (TD‐5959, GSK961081, batefenterol): first‐in‐class dual pharmacology multivalent muscarinic antagonist and beta(2) agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD). J Med Chem. 2015;58(6):2609–2622.
    1. Hughes AD, Jones LH. Dual‐pharmacology muscarinic antagonist and beta(2) agonist molecules for the treatment of chronic obstructive pulmonary disease. Future Med Chem. 2011;3(13):1585–1605.
    1. Hughes SC, Shardlow PC, Hollis FJ, et al. Metabolism and disposition of fluticasone furoate, an enhanced‐affinity glucocorticoid, in humans. Drug Metab Dispos. 2008;36(11):2337–2344.
    1. Ambery C, Riddell K, Daley‐Yates P. Open‐label, randomized, 6‐way crossover, single‐dose study to determine the pharmacokinetics of batefenterol (GSK961081) and fluticasone furoate when administered alone or in combination. Clin Pharmacol Drug Dev. 2016;5(5):399–407.
    1. Allen A, Bal J, Moore A, Stone S, Tombs L. Bioequivalence and dose proportionality of inhaled fluticasone furoate. J Bioequiv Avail. 2014;6(1):24–32.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi