Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airways diseases, adrenergics in combination with corticosteroids or other drugs, excl. anticholinergics ATC code: R03AK10.

Mechanism of action

Fluticasone furoate and vilanterol represent two classes of medications (a synthetic corticosteroid and a selective, long-acting beta2-receptor agonist).

Pharmacodynamic effects

Fluticasone furoate
Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects asthma and COPD symptoms is not known.
Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (e.g. cytokines and chemokines involved in inflammation).

Vilanterol trifenatate

Vilanterol trifenatate is a selective long-acting, beta2-adrenergic agonist (LABA).
The pharmacologic effects of beta2-adrenoceptor agonist active substances, including vilanterol trifenatate, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’,5’-adenosine monophosphate (cyclic AMP).
Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Molecular interactions occur between corticosteroids and LABAs, whereby steroids activate the beta2- receptor gene, increasing receptor number and sensitivity and LABAs prime the glucocorticoid receptor for steroid-dependent activation and enhance cell nuclear translocation. These synergistic interactions are reflected in enhanced anti-inflammatory activity, which has been demonstrated in vitro and in vivo in a range of inflammatory cells relevant to the pathophysiology of both asthma and COPD. In peripheral blood mononuclear cells from subjects with COPD, a larger anti-inflammatory effect was seen in the presence of the combination of fluticasone furoate/vilanterol compared with fluticasone furoate alone at concentrations achieved with clinical doses. The enhanced anti-inflammatory effect of the LABA component was similar to that obtained with other ICS/LABA combinations.


Clinical efficacy and safety
Asthma

Three phase III randomised, double-blind studies (HZA106827, HZA106829 and HZA106837) of different durations evaluated the safety and efficacy of fluticasone furoate/vilanterol in adult and adolescent patients with persistent asthma. All subjects were using an ICS (Inhaled corticosteroid) with or without LABA for at 
least 12 weeks prior to visit 1. In HZA106837 all patients had at least one exacerbation that required treatment with oral corticosteroids in the year prior to visit 1. HZA106827 was 12 weeks in duration and evaluated the efficacy of fluticasone furoate/vilanterol 92/22 micrograms [n=201] and FF 92 micrograms [n=205]) compared with placebo [n=203], all administered once daily. HZA106829 was 24 weeks in duration and evaluated the efficacy of fluticasone furoate/vilanterol 184/22 micrograms [n=197] and FF 184 micrograms [n=194]) both administered once daily compared with FP 500 micrograms twice daily [n=195].

In HZA106827/HZA106829 the co-primary efficacy endpoints were change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at the end of the treatment period in all subjects and weighted mean serial FEV1 over 0-24 hours post-dose calculated in a subset of subjects at the end of the treatment period. Change from baseline in the percentage of rescue-free 24 hour periods during treatment was a powered secondary endpoint. Results for the primary and key secondary endpoints in these studies are described in Table 1.
Table 1 - Results of primary and key secondary endpoints in HZA106827 and HZA106829 Study No.                             HZA106829                   HZA106827 Treatment Dose of           FF/VI 184/22 FF/VI 184/22    FF/VI 92/22    FF/VI 92/22 FF/VI*(micrograms)         Once Daily vs    Once Daily   Once Daily     Once Daily FF 184 Once      vs FP 500     vs FF 92      vs placebo
Daily      Twice Daily  Once Daily     Once Daily
Change from Baseline in Trough FEV1 Last Observation Carried Forward (LOCF) Treatment difference           193 mL          210 mL        36 mL         172 mL P value                        p<0.001         p<0.001     p=0.405         p<0.001 (95% CI)                      (108, 277)     (127, 294)   (-48, 120)      (87, 258) Weighted Mean Serial FEV1 over 0-24 hours post-dose
Treatment difference           136 mL          206 mL       116 mL         302 mL P value                        p=0.048         p=0.003      p=0.06         p<0.001 (95% CI)                       (1, 270)       (73, 339)    (-5, 236)     (178, 426) Change from Baseline in Percentage of Rescue-Free 24-hour Periods
Treatment difference            11.7%           6.3%         10.6%          19.3% P value                        p<0.001         p=0.067     p<0.001         p<0.001 (95% CI)                      (4.9, 18.4)   (-0.4, 13.1)  (4.3, 16.8)   (13.0, 25.6) Change from Baseline in Percentage of Symptom-Free 24-hour Periods
Treatment difference             8.4%           4.9%         12.1%          18.0% P value                        p=0.010         p=0.137     p<0.001         p<0.001 (95% CI)                      (2.0, 14.8)   (-1.6, 11.3)  (6.2, 18.1)   (12.0, 23.9) Change from Baseline in AM Peak Expiratory Flow
Treatment difference         33.5 L/min     32.9 L/min   14.6 L/min     33.3 L/min P value                        p<0.001         p<0.001     p<0.001         p<0.001 (95% CI)                     (22.3, 41.7)   (24.8, 41.1)  (7.9, 21.3)   (26.5, 40.0) Change from Baseline in PM Peak Expiratory Flow
Treatment difference         30.7 L/min     26.2 L/min   12.3 L/min     28.2 L/min P value                        p<0.001         p<0.001     p<0.001         p<0.001 (95% CI)                     (22.5, 38.9)   (18.0, 34.3)  (5.8, 18.8)   (21.7, 34.8) *FF/VI = fluticasone furoate/vilanterol

HZA106837 was of variable treatment duration (from a minimum of 24 weeks to a maximum of 76 weeks with the majority of patients treated for at least 52 weeks). In HZA106837 patients were randomised to receive either fluticasone furoate/vilanterol 92/22 micrograms [n=1009] or FF 92 micrograms [n=1010] both administered once daily. In HZA106837 the primary endpoint was the time to first severe asthma exacerbation. A severe asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Adjusted mean change from baseline in trough FEV1 was also evaluated as a secondary endpoint.

In HZA106837 the risk of experiencing a severe asthma exacerbation in patients receiving fluticasone furoate/vilanterol 92/22 micrograms was reduced by 20% compared with FF 92 micrograms alone (hazard ratio 0.795, p=0.036 95% CI 0.642, 0.985). The rate of severe asthma exacerbations per patient per year was 0.19 in the FF 92 micrograms group (approximately 1 in every 5 years) and 0.14 in the fluticasone furoate/vilanterol 92/22 micrograms group (approximately 1 in every 7 years). The ratio of the exacerbation rate for fluticasone furoate/vilanterol 92/22 micrograms versus FF 92 micrograms was 0.755 (95% CI 0.603, 0.945). This represents a 25% reduction in the rate of severe asthma exacerbations for subjects treated with fluticasone furoate/vilanterol 92/22 micrograms compared with FF 92 micrograms(p=0.014). The 24-hour bronchodilator effect of fluticasone furoate/vilanterol was maintained throughout a one-year treatment period with no evidence of loss in efficacy (no tachyphylaxis). Fluticasone furoate/vilanterol 92/22 micrograms consistently demonstrated 83 mL to 95 mL improvements in trough FEV1 at weeks 12, 36 and 52 and Endpoint compared with FF 92 micrograms (p<0.001 95% CI 52, 126 mL at Endpoint). Forty four percent of patients in the fluticasone furoate/vilanterol 92/22 micrograms group were well controlled (ACQ7 ≤0.75) at end of treatment compared to 36% of subjects in the FF 92 micrograms group (p<0.001 95% CI 1.23, 1.82).

Studies versus salmeterol/fluticasone propionate combinations

In a 24 week study (HZA113091) in adult and adolescent patients with uncontrolled persistent asthma both fluticasone furoate/vilanterol 92/22 micrograms given once daily in the evening and salmeterol/FP 50/250 micrograms given twice daily demonstrated improvements from baseline in lung function. Adjusted mean treatment increases from baseline in weighted mean 0-24 hours FEV1 of 341 mL (fluticasone furoate/vilanterol) and 377 mL (salmeterol/FP) demonstrated an overall improvement in lung function over 24 hours for both treatments. The adjusted mean treatment difference of 37 mL between the groups was not statistically significant (p=0.162). For trough FEV1 subjects in the fluticasone furoate/vilanterol group achieved a LS mean change from baseline of 281 mL and subjects in the salmeterol/FP group a change of 300 mL; (the difference in adjusted mean of 19 mL (95%CI:-0.073, 0.034) was not statistically significant (p=0.485).

A randomised, double-blind, parallel group, 24 week study (201378) was conducted to demonstrate non- inferiority (using a margin of -100 mL for trough FEV1) of fluticasone furoate/vilanterol 92/22 micrograms once daily to salmeterol/FP 50/250 micrograms twice daily in adults and adolescents whose asthma was well controlled following 4 weeks of treatment with open-label salmeterol/FP 50/250 micrograms twice daily (N=1504). Subjects randomised to once-daily FF/VI maintained lung function comparable with those randomised to twice-daily salmeterol/FP [difference in trough FEV1 of +19 mL (95% CI: -11, 49)].

No comparative studies versus salmeterol/FP or versus other ICS/LABA combinations have been conducted to appropriately compare the effects on asthma exacerbations.

Fluticasone furoate monotherapy

A 24 week randomised, double-blind placebo controlled study (FFA112059) evaluated the safety and efficacy of FF 92 micrograms once daily [n= 114] and FP 250 micrograms twice daily [n=114] versus placebo [n=115] in adult and adolescent patients with persistent asthma. All subjects had to have been on a stable dose of an ICS for at least 4 weeks prior to visit 1 (screening visit) and the use of LABAs was not permitted within 4 weeks of visit 1. The primary efficacy endpoint was change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at the end of the treatment period. Change from baseline in the percentage of rescue-free 24-hour periods during the 24-week treatment period was a powered secondary.
At the 24-week time point FF and FP increased trough FEV1 by 146 mL (95% CI 36, 257 mL, p=0.009) and 145 mL (95% CI 33, 257 mL, p=0.011) respectively compared to placebo. FF and FP both increased the percentage of 24-hour rescue-free periods by 14.8% (95% CI 6.9, 22.7, p<0.001) and 17.9% (95% CI 10.0, 25.7, p<0.001) respectively versus placebo.

Allergen challenge study


The bronchoprotective effect of fluticasone furoate/vilanterol 92/22 micrograms on the early and late asthmatic response to inhaled allergen was evaluated in a repeat dose, placebo-controlled four-way crossover study (HZA113126) in patients with mild asthma. Patients were randomized to receive fluticasone furoate/vilanterol 92/22 micrograms, FF 92 micrograms, vilanterol 22 micrograms or placebo once daily for 21 days followed by challenge with allergen 1 hour after the final dose. The allergen was house dust mite, cat dander, or birch pollen; the selection was based on individual screening tests. Serial FEV1 measurements were compared with pre-allergen challenge values taken after saline inhalation (baseline). Overall, the greatest effects on the early asthmatic response were seen with fluticasone furoate/vilanterol 92/22 micrograms compared with FF 92 micrograms or vilanterol 22 micrograms alone. Both fluticasone furoate/vilanterol 92/22 micrograms and FF 92 micrograms virtually abolished the late asthmatic response compared with vilanterol alone. Fluticasone furoate/vilanterol 92/22 micrograms provided significantly greater protection against allergen-induced bronchial hyper-reactivity compared with monotherapies FF and vilanterol as assessed on Day 22 by methacholine challenge.

Bronchoprotective and HPA-axis effects study

The bronchoprotective and HPA-axis effects of FF versus FP or budesonide (BUD) were evaluated in an escalating repeat-dose, placebo-controlled, crossover study (203162) in 54 adults with a history of asthma, characterised by airway hyperresponsiveness and FEV1 ≥65% predicted. Patients were randomised to one or two treatment periods, comprising five 7-day dose-escalation phases of FF (25, 100, 200, 400, 800 micrograms/day), FP (50, 200, 500, 1,000, 2,000 micrograms/day), BUD (100, 400, 800, 1,600, 3,200 micrograms/day), or placebo. After each dose-escalation phase, bronchoprotection via airway hyperresponsiveness to adenosine-5'-monophosphate (AMP) challenge (provocative concentration causing ≥20% decline in FEV1 [AMP PC20]) and 24-hour weighted mean plasma cortisol were assessed.

Across the approved therapeutic dose ranges for asthma the AMP PC20 (mg/mL) and cortisol suppression (%) values were: 81 to 116 mg/mL and 7% to 14% for FF (100 to 200 micrograms/day), 20 to 76 mg/mL and 7% to 50% for FP (200 to 2,000 micrograms/day), and 24 to 54 mg/mL and 13% to 44% for BUD (400 to 1,600 micrograms/day), respectively.


Chronic Obstructive Pulmonary Disease
The COPD clinical development programme included a 12-week (HZC113107), two 6-month (HZC112206, HZC112207), two one-year (HZC102970, HZC102871), and one >1 year study (SUMMIT). These were randomised controlled studies in patients with a clinical diagnosis of COPD. These studies included measures of lung function, dyspnoea and moderate and severe exacerbations.

Six month studies

HZC112206 and HZC112207 were 24 week randomised, double-blind, placebo controlled, parallel group studies comparing the effect of the combination to vilanterol and FF alone and placebo. HZC112206 evaluated the efficacy of fluticasone furoate/vilanterol 46 /22 micrograms [n=206] and fluticasone furoate/vilanterol 92/22 micrograms [n=206] compared with FF 92 micrograms [n=206], vilanterol 22 micrograms [n=205] and placebo [n = 207], all administered once daily. HZC112207 evaluated the efficacy of fluticasone furoate/vilanterol 92/22 micrograms [n=204] and fluticasone furoate/vilanterol 184/22 micrograms [n=205] compared with FF 92 micrograms [n=204], FF 184 micrograms [n=203] and vilanterol 22 micrograms [n=203] and placebo [n = 205], all administered once daily.

All patients were required to have a smoking history of at least 10 pack years; a post-salbutamol FEV1/FVC ratio less than or equal to 0.70; post-salbutamol FEV1 less than or equal to 70% predicted and have a Modified Medical Research Council (mMRC) dyspnea score 2 (scale 0-4) at screening. At screening, the mean pre-bronchodilator FEV1 was 42.6% and 43.6% predicted, and the mean reversibility was 15.9% and 12.0% in HZC112206 and HZC112207, respectively. The co-primary endpoints in both studies were weighted mean FEV1 from zero to 4 hours post-dose at Day 168 and change from baseline in pre-dose trough FEV1 at Day 169.

In an integrated analysis of both studies, fluticasone furoate/vilanterol 92/22 micrograms showed clinically meaningful improvements in lung function. At Day 169 fluticasone furoate/vilanterol 92/22 micrograms and vilanterol increased adjusted mean trough FEV1 by 129 mL (95% CI: 91, 167 mL, p<0.001) and 83 mL (95% CI: 46, 121 mL, p<0.001) respectively compared to placebo. Fluticasone furoate/vilanterol 92/22 micrograms increased trough FEV1 by 46 mL compared to vilanterol (95% CI: 8, 83 mL, p= 0.017).
At Day 168 fluticasone furoate/vilanterol 92/22 micrograms and vilanterol increased adjusted mean weighted mean FEV1 over 0-4 hours by 193 mL (95% CI: 156, 230 mL, p<0.001) and 145 mL (95% CI: 108, 181 mL, p<0.001) respectively compared to placebo. Fluticasone furoate/vilanterol 92/22 micrograms increased adjusted mean weighted mean FEV1 over 0-4 hours by 148 mL compared to FF alone (95% CI: 112, 184 mL, p< 0.001).

12 month studies

Studies HZC102970 and HZC102871 were 52 week randomised, double-blind, parallel-group, studies comparing the effect of fluticasone furoate/vilanterol 184/22 micrograms, fluticasone furoate/vilanterol 92/22 micrograms, fluticasone furoate/vilanterol 46/22 micrograms with vilanterol 22 micrograms, all administered once daily, on the annual rate of moderate/severe exacerbations in subjects with COPD with a smoking history of at least 10 pack years and a post-salbutamol FEV1/FVC ratio less than or equal to 0.70 and post-salbutamol FEV1 less than or equal to 70% predicted and documented history of ≥ 1 COPD exacerbation that required antibiotics and/or oral corticosteroids or hospitalisation in the 12 months prior to visit 1. The primary endpoint was the annual rate of moderate and severe exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. Both studies had a 4 week run-in period during which all subjects received open-label salmeterol/FP 50/250 micrograms twice daily to standardise COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies.

The results of both studies showed that treatment with fluticasone furoate/vilanterol 92/22 micrograms once daily resulted in a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol (Table 2).



Table 2: Analysis of Exacerbation Rates following 12 months of treatment HZC102970                     HZC102871                  HZC102970 and HZC102871 integrated fluticasone                         fluticasone                fluticasone furoate/                            furoate/                   furoate/ Vilanterol                        Vilanterol                     Vilanterol vilanterol                          vilanterol                 vilanterol (n=409)                           (n=409)          92/22         (n=818) Endpoint                        92/22                                                          92/22 (n=403)                             (n=403)                    (n=806) Moderate and severe exacerbations
Adjusted mean     1.14           0.90              1.05            0.70           1.11           0.81 annual rate
Ratio vs VI                      0.79                               0.66                          0.73 95% CI                      (0.64,0.97)                         (0.54, 0.81)                  (0.63, 0.84) p-value                         0.024                              <0.001                        <0.001 % reduction                       21                                 34                            27 (95% CI)                       (3, 36)                            (19, 46)                      (16, 37) Absolute difference in number per year vs VI
(95% CI)                         0.24                               0.36                          0.30 (0.03, 0.41)                         (0.20, 0.48)                  (0.18, 0.41) Time to first exacerbation:
Hazard ratio                     0.80                               0.72                          0.76 (95% CI)                   (0.66, 0.99)                         (0.59, 0.89)                  (0.66, 0.88) % risk                            20                                 28                            24 reduction
 p-value                            0.036                           0.002                        p<0.001 
In an integrated analysis of HZC102970 and HZC102871 at Week 52, an improvement was seen when comparing the fluticasone furoate/vilanterol 92/22 micrograms versus vilanterol 22 micrograms in adjusted mean trough FEV1 (42 mL 95% CI: 19, 64 mL, p<0.001). The 24-hour bronchodilator effect of fluticasone furoate/vilanterol was maintained from the first dose throughout a one-year treatment period with no evidence of loss in efficacy (no tachyphylaxis).

Overall, across the two studies combined 2009 (62%) patients had cardiovascular history/risk factors at screening. The incidence of cardiovascular history/risk factors was similar across the treatment groups with patients most commonly suffering from hypertension (46%), followed by hypercholesterolemia (29%) and diabetes mellitus (12%). Similar effects in reduction of moderate and severe exacerbations were observed in this subgroup as compared with the overall population. In patients with a cardiovascular history/risk factors, fluticasone furoate/vilanterol 92/22 micrograms resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with vilanterol (adjusted mean annual rates of 0.83 and 1.18 respectively, 30% reduction (95% CI 16, 42%, p<0.001)). Improvements were also seen in this subgroup at Week 52 when comparing the fluticasone furoate/vilanterol 92/22 micrograms vs. vilanterol 22 micrograms in adjusted mean trough FEV1 (44 mL 95% CI: 15, 73 mL, (p=0.003)).


Studies > 1 year duration
SUMMIT was a multi-centre, randomised, double-blind study evaluating the effect on survival of fluticasone furoate/vilanterol 92/22 micrograms compared with placebo in 16,485 subjects. The primary endpoint was all-cause mortality and a secondary endpoint was a composite of cardiovascular events (on-treatment cardiovascular death, myocardial infarction, stroke, unstable angina, or transient ischemic attack).

Prior to randomization, subjects were required to discontinue previous COPD medications used at baseline, which included long-acting bronchodilators plus inhaled corticosteroids (28%), long-acting bronchodilators alone (11%) and inhaled corticosteroids alone (4%). Subjects were then randomized to receive either fluticasone furoate/vilanterol 92/22 micrograms, fluticasone furoate 92 micrograms, vilanterol 22 micrograms, or placebo, and treated for a mean of 1.7 years (SD = 0.9 years).

Subjects had moderate COPD (mean percent post-bronchodilator screening FEV1 of 60% [SD = 6%]), and a history of, or an increased risk of cardiovascular disease. In the 12 months prior to the study, 61% of subjects reported no COPD exacerbations and 39% of subjects reported ≥1 moderate/severe COPD exacerbation.

All-cause mortality was: fluticasone furoate/vilanterol, 6.0%; placebo, 6.7%; fluticasone furoate, 6.1%; vilanterol, 6.4%. Exposure-adjusted all-cause mortality per 100 patients/year (%/yr) was: fluticasone furoate/vilanterol, 3.1 %/yr; placebo, 3.5 %/yr; fluticasone furoate, 3.2 %/yr; and vilanterol, 3.4 %/yr.
Mortality risk with fluticasone furoate/vilanterol was not significantly different compared with placebo (HR 0.88; 95% CI: 0.74 to 1.04; p=0.137), fluticasone furoate (HR 0.96; 95% CI: 0.81 to 1.15; p=0.681) or vilanterol (HR 0.91; 95% CI: 0.77 to 1.09; p=0.299).

The risk of the cardiovascular composite event with fluticasone furoate/vilanterol was not significantly different compared with placebo (HR 0.93; 95% CI: 0.75 to 1.14), fluticasone furoate (HR 1.03; 95% CI: 0.83 to 1.28) or vilanterol (HR 0.94; 95% CI: 0.76 to 1.16).

Studies versus salmeterol/fluticasone propionate combinations

In a 12 week study (HZC113107) in COPD patients both fluticasone furoate/vilanterol 92/22 micrograms given once daily in the morning and salmeterol/FP 50/500 micrograms given twice daily, demonstrated improvements from baseline in lung function. Adjusted mean treatment increases from baseline in weighted mean 0-24 hours FEV1 of 130 mL (fluticasone furoate/vilanterol) and 108 mL (salmeterol/FP) demonstrated an overall improvement in lung function over 24 hours for both treatments. The adjusted mean treatment difference of 22 mL (95% CI: -18, 63 mL) between the groups was not statistically significant (p=0.282).
The adjusted mean change from baseline in trough FEV1 on Day 85 was 111 mL in the fluticasone furoate/vilanterol group and 88 mL in the salmeterol/FP group; the 23 mL (95% CI: -20, 66) difference between the treatment groups was not clinically meaningful or statistically significant (p=0.294).
No comparative studies versus salmeterol/FP or versus other established bronchodilators have been conducted to appropriately compare the effects on COPD exacerbations.

Paediatric population

Asthma
The efficacy and safety of fluticasone furoate (FF)/vilanterol (VI) administered once daily compared to FF administered once daily in the treatment of asthma in paediatric patients aged 5-11 years was evaluated in a randomised, double-blind, multicentre clinical trial of 24 weeks duration and 1 week follow-up period (HZA107116) involving 673 patients with uncontrolled asthma, on inhaled corticosteroids.
All subjects had stable asthma therapy [short-acting beta agonist or short-acting muscarinic antagonist inhaler plus inhaled corticosteroid (ICS)] for at least 4 weeks prior to Visit 1. Patients were symptomatic (i.e., remained uncontrolled) on their existing asthma treatment.
Subjects were treated with fluticasone furoate/vilanterol 46/22 micrograms (337 patients) or fluticasone furoate 46 micrograms (336 patients). Two patients, one in each arm, were not assessable for efficacy.
The primary endpoint was change from baseline, averaged over weeks 1 to 12 of the treatment period, in pre- dose (i.e., trough) morning peak expiratory flow (PEF), captured daily via electronic patient diary (difference between FF/VI combination and FF). Change from baseline in the percentage of rescue-free 24-hour periods over weeks 1 to 12 of the treatment period was a powered secondary endpoint for the 5-11 years population.
There were no differences in efficacy between FF/VI 46/22 micrograms and FF 46 micrograms (Table 3). No new safety concerns were identified during this study.


After study HZA107116 completed, concerns regarding the conduct of the study at two study sites were identified, involving total of 4 randomised patients (FF/VI 46/22 micrograms n= 1, FF 46 micrograms n = 3).
A post-hoc supplementary analysis, excluding these 4 patients, was performed.
The results of this analysis (Table 3) are consistent with those of the pre-defined analysis.

Table 3: Results of primary and powered secondary endpoints (post-hoc supplementary analysis).

Weeks 1 to 12                                    Fluticasone furoate/Vilanterol*   Fluticasone furoate* n=335                        n=332
Primary endpoint
Change from Baseline in AM PEF (L/min)
LS Mean Change (SE)                                       12.1 (1.86)                   8.6 (1.87) Treatment difference (FF/VI vs FF)                                          3.5 (95% CI), p-value                                                  (-1.7, 8.7), p=0.188 Powered secondary endpoint
Change from Baseline in Percentage of Rescue-free 24-hour Periods
LS Mean Change (SE)                                       27.1 (1.75)                   26.0 (1.76) Treatment difference (FF/VI vs FF)                                          1.1 (95% CI), p-value                                                  (-3.8, 6.0), p=0.659 *Patients were receiving FF/VI 46/22 micrograms OD vs FF 46 micrograms OD OD = Once Daily, LS = least squares, SE = standard error, CI = confidence interval, n = number of participants in analysis (All ITT: 337 for FF/VI and 336 for FF)

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

The absolute bioavailability for fluticasone furoate and vilanterol when administered by inhalation as fluticasone furoate/vilanterol was on average 15.2% and 27.3%, respectively. The oral bioavailability of both fluticasone furoate and vilanterol was low, on average 1.26% and <2%, respectively. Given this low oral bioavailability, systemic exposure for fluticasone furoate and vilanterol following inhaled administration is primarily due to absorption of the inhaled portion of the dose delivered to the lung.

Distribution

Following intravenous dosing, both fluticasone furoate and vilanterol are extensively distributed with average volumes of distribution at steady state of 661 L and 165 L, respectively.
Both fluticasone furoate and vilanterol have a low association with red blood cells. In vitro plasma protein binding in human plasma of fluticasone furoate and vilanterol was high, on average >99.6% and 93.9%, respectively. There was no decrease in the extent of in vitro plasma protein binding in subjects with renal or hepatic impairment.
Fluticasone furoate and vilanterol are substrates for P-glycoprotein (P-gp), however, concomitant administration of fluticasone furoate/vilanterol with P-gp inhibitors is considered unlikely to alter fluticasone furoate or vilanterol systemic exposure since they are both well absorbed molecules.

Biotransformation

Based on in vitro data, the major routes of metabolism of both fluticasone furoate and vilanterol in human are mediated primarily by CYP3A4.



Fluticasone furoate is primarily metabolised through hydrolysis of the S-fluoromethyl carbothioate group to metabolites with significantly reduced corticosteroid activity. Vilanterol is primarily metabolised by O-dealkylation to a range of metabolites with significantly reduced β1- and β2-agonist activity.

Elimination

Following oral administration, fluticasone furoate was eliminated in humans mainly by metabolism with metabolites being excreted almost exclusively in faeces, with <1% of the recovered radioactive dose eliminated in the urine.

Following oral administration, vilanterol was eliminated mainly by metabolism followed by excretion of metabolites in urine and faeces approximately 70% and 30% of the radioactive dose respectively in a human radiolabel study conducted by the oral route. The apparent plasma elimination half-life of vilanterol following single inhaled administration of fluticasone furoate/vilanterol was, on average, 2.5 hours. The effective half-life for accumulation of vilanterol, as determined from inhalation administration of repeat doses of vilanterol 25 micrograms, is 16.0 hours in subjects with asthma and 21.3 hours in subjects with COPD.

Paediatric population

In adolescents (12 years or older), there are no recommended dose modifications.
The pharmacokinetics, safety and efficacy of fluticasone furoate/vilanterol have been studied in children from 5 to 11 years old, but no recommendation on a posology can be made (see section 4.2). The pharmacokinetics, safety and efficacy of fluticasone furoate/vilanterol in children under the age of 5 years have not been established.
Special populations

Elderly

The effects of age on the pharmacokinetics of fluticasone furoate and vilanterol were determined in phase III studies in COPD and asthma. There was no evidence for age (12 to 84 years) to affect the pharmacokinetics of fluticasone furoate and vilanterol in subjects with asthma.

There was no evidence for age to affect the pharmacokinetics of fluticasone furoate in subjects with COPD while there was an increase (37%) in AUC (0-24) of vilanterol over the observed age range of 41 to 84 years.
For an elderly subject (aged 84 years) with low bodyweight (35 kg) vilanterol AUC (0-24) is predicted to be 35% higher than the population estimate (subject with COPD aged 60 years and bodyweight of 70 kg), whilst Cmax was unchanged. These differences are unlikely to be of clinical relevance.
In elderly subjects with asthma and elderly subjects with COPD there are no recommended dose modifications.

Renal impairment

A clinical pharmacology study of fluticasone furoate/vilanterol showed that severe renal impairment (creatinine clearance <30 mL/min) did not result in significantly greater exposure to fluticasone furoate or vilanterol or more marked corticosteroid or beta2-agonist systemic effects compared with healthy subjects.

No dose adjustment is required for patients with renal impairment.

The effects of haemodialysis have not been studied.
Hepatic impairment

Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (up to three-fold as measured by AUC(0–24)) in subjects with hepatic impairment (Child-Pugh A, B or C) compared with healthy subjects. The increase in fluticasone furoate systemic exposure in subjects with moderate hepatic impairment (Child-Pugh B; fluticasone furoate/vilanterol 184/22 micrograms) was associated with an average 34% reduction in serum cortisol compared with healthy subjects. Dose-normalised fluticasone furoate systemic exposure was similar in subjects with moderate and severe hepatic impairment (Child-Pugh B or C).

Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was no significant increase in systemic exposure to vilanterol (Cmax and AUC) in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh A, B or C).

There were no clinically relevant effects of the fluticasone furoate/vilanterol combination on beta-adrenergic systemic effects (heart rate or serum potassium) in subjects with mild or moderate hepatic impairment (vilanterol, 22 micrograms) or with severe hepatic impairment (vilanterol, 12.5 micrograms) compared with healthy subjects.

Other special populations

In subjects with asthma, estimates of fluticasone furoate AUC(0-24) for East Asian, Japanese and South East Asian subjects (12-13% of subjects) were on average 33% to 53% higher compared with other racial groups.
However, there was no evidence for the higher systemic exposure in this population to be associated with greater effect on 24 hour urinary cortisol excretion. On average, vilanterol Cmax is predicted to be 220 to 287% higher and AUC(0-24) comparable for those subjects from an Asian heritage compared with subjects from other racial groups. However, there was no evidence that this higher vilanterol Cmax resulted in clinically significant effects on heart rate.
In subjects with COPD estimates of fluticasone furoate AUC(0-24) for East Asian, Japanese and South East Asian subjects (13-14% subjects) were on average 23% to 30% higher compared with Caucasian subjects.
However, there was no evidence for the higher systemic exposure in this population to be associated with greater effect on 24 hour urinary cortisol excretion. There was no effect of race on pharmacokinetic parameter estimates of vilanterol in subjects with COPD.

Gender, weight and BMI

There was no evidence for gender, weight or BMI (body mass index) to influence the pharmacokinetics of fluticasone furoate based on a population pharmacokinetic analysis of phase III data in 1213 subjects with asthma (712 females) and 1225 subjects with COPD (392 females).

There was no evidence for gender, weight or BMI to influence the pharmacokinetics of vilanterol based on a population pharmacokinetic analysis in 856 subjects with asthma (500 females) and 1091 subjects with COPD (340 females).

No dosage adjustment is necessary based on gender, weight or BMI.