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

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AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 10/2007; 293(3):L660-7. DOI: 10.1152/ajplung.00108.2007
Source: PubMed


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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    • "FF (formerly drug code GW685698) is a novel enhanced-affinity synthetic trifluorinated glucocorticoid.25 X-ray crystallography comparison studies of its structure with that of dexamethasone and FP have demonstrated that the 17-α furoate ester occupies more fully the lipophilic 17-α pocket on the ligand binding domain of GR, and this may account for the enhanced GR binding of FF26 "
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    ABSTRACT: Currently, there is no cure for chronic obstructive pulmonary disease (COPD). The limited efficacy of current therapies for COPD indicates a pressing need to develop new treatments to prevent the progression of the disease, which consumes a significant amount of health care resources and is an important cause of mortality worldwide. Current national and international guidelines for the management of stable COPD patients recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids, and their combination for maintenance treatment of moderate to severe stable COPD. Once-daily fluticasone furoate/vilanterol dry powder inhaler combination therapy has recently been approved by the US Food and Drug Administration and the European Medicines Agency as a new regular treatment for patients with stable COPD. Fluticasone furoate/vilanterol dry powder inhaler combination therapy has been shown to be effective in many controlled clinical trials involving thousands of patients in the regular treatment of stable COPD. This is the first once-daily combination of ultra-long-acting inhaled β2-agonists and inhaled glucocorticoids that is available for the treatment of stable COPD and has great potential to improve compliance to long-term regular inhaled therapy and hence to improve the natural history and prognosis of COPD patients.
    International Journal of COPD 02/2014; 9:249-256. DOI:10.2147/COPD.S32604 · 3.14 Impact Factor
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    • "Structurally, FF is distinct from the twice-daily (BD) ICS, fluticasone propionate (FP) [4]. Preclinically, FF exhibits a greater antiinflammatory activity than FP [5] [6]. Clinically, FF, administered once-daily in the evening is non-inferior to the same daily dose administered twice daily with respect to lung function [7]; exhibits significant effects versus placebo with respect to lung function over a range of doses and asthma severities [8e10]; has shown a significant effect on the allergen-induced early asthmatic response 23e24 h after dosing [11]; and is indicated as a once-daily therapy for allergic rhinitis [12] [13]. "
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    ABSTRACT: Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 μg OD), 42% (FP250 μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 μg OD (3%) and FP250 μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 μg OD (p = 0.030) and FP250 μg BD (p = 0.036) relative to placebo. FF100 μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 μg BD with similar safety profile.
    Respiratory medicine 11/2013; 108(1). DOI:10.1016/j.rmed.2013.11.009 · 3.09 Impact Factor
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    • "At the C-17α position, FF contains an ester derived from 2-furoic acid which replaces the simpler propionate ester. These differences mean that FF has more complete occupancy of the 17α pocket in the glucocorticoid receptor [12] and higher glucocorticoid receptor binding affinity than FP [13]. As part of the overall phase II development plan investigating FF, dose-ranging studies in asthma patients have demonstrated that FF has a favourable efficacy and safety profile when administered once-daily in the evening [14-16]. "
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    ABSTRACT: Inhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD) evening and twice-daily (BD) regimens of the novel inhaled corticosteroid fluticasone furoate (FF) in asthma patients. Patients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1) 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml) were randomized to FF or fluticasone propionate (FP) regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough) FEV1; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs) and 24-hour urinary cortisol excretion were assessed. The intent-to-treat population comprised 147 (FF) and 43 (FP) patients. On Day 28, pre-dose FEV1 showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml) to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml); all FF and FP regimens were significantly superior to placebo (p ≤ 0.02). AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02). FF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose.; NCT00766090.
    Respiratory research 12/2011; 12(1):160. DOI:10.1186/1465-9921-12-160 · 3.09 Impact Factor
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