Integrated safety and efficacy analysis of once-daily fluticasone furoate for the treatment of asthma

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Abstract

Background

Fluticasone furoate is a once-daily inhaled corticosteroid. This report provides an overview of safety and efficacy data that support the use of once-daily fluticasone furoate 100 μg or 200 μg in adult and adolescent asthma patients.

Methods

Fourteen clinical studies (six Phase II and eight Phase III) were conducted as part of the fluticasone furoate global clinical development programme in asthma. Safety data from 10 parallel-group, randomised, double-blind Phase II and III studies (including 3345 patients who received at least one dose of fluticasone furoate) were integrated to provide information on adverse events, withdrawals, laboratory assessments, vital signs and hypothalamic-pituitary-adrenal axis function. The efficacy of once-daily fluticasone furoate was evaluated in all included studies.

Results

Once-daily fluticasone furoate 100 μg and 200 μg safety profiles were consistent with those reported for other inhaled corticosteroids, and both doses consistently demonstrated efficacy versus placebo. In the integrated analysis, no dose-response relationship was observed for the overall incidence of adverse events and there were no significant effects of fluticasone furoate on hypothalamic-pituitary-adrenal axis function.

Conclusion

Once-daily fluticasone furoate 100 μg and 200 μg had acceptable safety profiles and was efficacious in adult and adolescent patients with asthma. There was no evidence of cortisol suppression at studied doses.

Trial registrations

GSK (NCT01499446/FFA20001, NCT00398645/FFA106783, NCT00766090/112202, NCT00603746/FFA109684, NCT00603278/FFA109685, NCT00603382/FFA109687, NCT01436071/115283, NCT01436110/115285, NCT01159912/112059, NCT01431950/114496, NCT01165138/HZA106827, NCT01086384/106837, NCT01134042/HZA106829 and NCT01244984/1139879).

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-016-0473-x) contains supplementary material, which is available to authorized users.

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Most cited references 25

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Inhaled corticosteroids: potency, dose equivalence and therapeutic index

Peter Daley-Yates (2015)

Glucocorticosteroids are a group of structurally related molecules that includes natural hormones and synthetic drugs with a wide range of anti-inflammatory potencies. For synthetic corticosteroid analogues it is commonly assumed that the therapeutic index cannot be improved by increasing their glucocorticoid receptor binding affinity. The validity of this assumption, particularly for inhaled corticosteroids, has not been fully explored. Inhaled corticosteroids exert their anti-inflammatory activity locally in the airways, and hence this can be dissociated from their potential to cause systemic adverse effects. The molecular structural features that increase glucocorticoid receptor binding affinity and selectivity drive topical anti-inflammatory activity. However, in addition, these structural modifications also result in physicochemical and pharmacokinetic changes that can enhance targeting to the airways and reduce systemic exposure. As a consequence, potency and therapeutic index can be correlated. However, this consideration is not reflected in asthma treatment guidelines that classify inhaled corticosteroid formulations as low-, mid- and high dose, and imbed a simple dose equivalence approach where potency is not considered to affect the therapeutic index. This article describes the relationship between potency and therapeutic index, and concludes that higher potency can potentially improve the therapeutic index. Therefore, both efficacy and safety should be considered when classifying inhaled corticosteroid regimens in terms of dose equivalence. The historical approach to dose equivalence in asthma treatment guidelines is not appropriate for the wider range of molecules, potencies and device/formulations now available. A more robust method is needed that incorporates pharmacological principles.

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Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease.

Mark Salter, Keith Biggadike, J. Matthews … (2007)

Fluticasone furoate (FF) is a novel enhanced-affinity glucocorticoid that has been developed as topical therapy for allergic rhinitis. The pharmacological properties of FF have been investigated using a number of in vitro experimental systems. FF demonstrated very potent glucocorticoid activity in several key pathways downstream of the glucocorticoid receptor (GR) as follows: the transrepression nuclear factor-kappaB (NF-kappaB) pathway, the transactivation glucocorticoid response element pathway, and inhibition of the proinflammatory cytokine tumor necrosis factor-alpha. Furthermore, FF showed the greatest potency compared with other glucocorticoids for preserving epithelial integrity and reducing epithelial permeability in response to protease- and mechanical-induced cell damage. FF showed a 30- to >330,000-fold selectivity for GR-mediated inhibition of NF-kappaB vs. the other steroid hormone receptors, substantially better than a number of other clinically used glucocorticoids. In studies examining the respiratory tissue binding properties of glucocorticoids, FF had the largest cellular accumulation and slowest rate of efflux compared with other clinically used glucocorticoids, consistent with greater tissue retention. The in vivo anti-inflammatory activity of FF was assessed in the Brown Norway rat ovalbumin-induced lung eosinophilial model of allergic lung inflammation. At a dose of only 30 microg, FF achieved almost total inhibition of eosinophil influx in the lung, an inhibition that was greater than that seen with the same dose of fluticasone propionate. In conclusion, the potent and selective pharmacological profile of FF described here could deliver an effective, safe, and sustained topical treatment of respiratory inflammatory diseases such as allergic rhinitis and asthma.

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Risks of pneumonia in patients with asthma taking inhaled corticosteroids.

Stefan Peterson, A Thorén, Søren Pedersen … (2011)

Inhaled corticosteroids (ICS) are the mainstay of asthma treatment. Studies in chronic obstructive pulmonary disease reported increased rates of pneumonia with ICS. Concerns exist about an increased pneumonia risk in patients with asthma taking ICS. To evaluate the risks of pneumonia in patients with asthma taking ICS. A retrospective analysis evaluated studies of the ICS budesonide in asthma. The primary data set were all double-blind, placebo-controlled trials lasting at least 3 months, involving budesonide (26 trials, n = 9,067 for budesonide; n = 5,926 for the comparator) sponsored by AstraZeneca. A secondary data set evaluated all double-blind trials lasting at least 3 months but without placebo control (60 trials, n = 33,496 for budesonide, n = 2,773 for fluticasone propionate). Cox proportional hazards regression modeling was used to estimate the relative effect of ICS on pneumonia adverse events (AEs) or serious adverse events (SAEs). In the primary data set, the occurrence of pneumonia AEs was 0.5% (rate 10.0 events/1,000 patient-years [TPY]) for budesonide and 1.2% (19.3 per TPY) for placebo (hazard ratio, 0.52; 95% confidence interval, 0.36-0.76; P < 0.001); the occurrence of pneumonia SAEs was 0.15% (2.9 per TPY) for budesonide and 0.13% (2.1 per TPY) for placebo (hazard ratio, 1.29; 95% confidence interval, 0.53-3.12; P = 0.58). In the secondary data set, the percentage of patients reporting pneumonia AEs was 0.70% (12.7 per TPY), whereas the percentage of patients reporting pneumonia SAEs was 0.17% (3.1 per TPY). There was no increased risk with higher budesonide doses or any difference between budesonide and fluticasone. There is no increased risk of pneumonia in patients with asthma, identified as an AE or SAE, in clinical trials using budesonide.

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Author and article information

Contributors

Paul M. O’Byrne: +1 905 521 2100 , obyrnep@mcmaster.ca

Loretta Jacques: loretta.a.jacques@gsk.com

Caroline Goldfrad: caroline.h.goldfrad@gsk.com

Namhee Kwon: namhee.n.kwon@gsk.com

Michael Perrio: michael.j.perrio@gsk.com

Louisa J. Yates: louisa.j.yates@gsk.com

William W. Busse: Wwb@medicine.wisc.edu

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 24 November 2016

Publication date PMC-release: 24 November 2016

Publication date (Print): 2016

Volume: 17

Electronic Location Identifier: 157

Affiliations

[1 ]Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON Canada

[2 ]Respiratory Medicine Development Centre, GSK, London, TW8 9GS UK

[3 ]Quantitative Sciences Division, GSK, London, TW8 9GS UK

[4 ]Respiratory Franchise Medical, GSK, London, TW8 9GS UK

[5 ]Global Clinical Safety and Pharmacovigilance, GSK, TW8 9GS London, UK

[6 ]University of Wisconsin School of Medicine and Public Health, Madison, WI USA

[7 ]Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, 1280 Main Street West, Room 3W10, Hamilton, ON L8S 4K1 Canada

Article

Publisher ID: 473

DOI: 10.1186/s12931-016-0473-x

PMC ID: 5122018

PubMed ID: 27881132

SO-VID: f8a9f7f3-2043-4da4-a1f2-3c6b44699f21

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 May 2016

Date accepted : 10 November 2016

Funding

Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/501100002066, GlaxoSmithKline foundation;

Award ID: FFA20001, FFA106783, 112202, FFA109684, FFA109685, FFA109687, 115283, 115285, 112059, 114496, HZA106827, 106837, HZA106829, 1139879

Custom metadata

ScienceOpen disciplines: Respiratory medicine

Keywords: adverse events,cortisol suppression,fluticasone furoate,forced expiratory volume in one second,inhaled corticosteroid,integrated analysis,safety

Data availability:

ScienceOpen disciplines: Respiratory medicine

Keywords: adverse events, cortisol suppression, fluticasone furoate, forced expiratory volume in one second, inhaled corticosteroid, integrated analysis, safety

Integrated safety and efficacy analysis of once-daily fluticasone furoate for the treatment of asthma

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Abstract

Background

Methods

Results

Conclusion

Trial registrations

Electronic supplementary material

Related collections

Inflamed lung in vitro co-culture models

Most cited references 25

Inhaled corticosteroids: potency, dose equivalence and therapeutic index

Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease.

Risks of pneumonia in patients with asthma taking inhaled corticosteroids.

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Contributors

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