Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 PHARMACODYNAMIC PROPERTIES
Mechanism of action
Fluticasone furoate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and when administered intranasally, has a potent anti-inflammatory action in the airway.
Clinical trials
Seasonal and Perennial Allergic Rhinitis in Adults and Adolescents (12 years and over)

Five randomised, double blind, parallel group, placebo-controlled trials have investigated the safety and efficacy of AVAMYS nasal spray 110 micrograms once daily in adults and adolescents 12 years of age and older with symptoms of seasonal or perennial allergic rhinitis. The five trials include one 2-week dose-ranging trial in patients with seasonal allergic rhinitis (FFR20001), three 2-week efficacy trials in patients with seasonal allergic rhinitis (FFR30003, FFR103184, FFR104861), and one 4-week efficacy trial in patients with perennial allergic rhinitis (FFR30002).
The primary efficacy variable for all studies was based on the daily assessment of four nasal symptoms (rhinorrhoea, nasal congestion, nasal itching and sneezing) using a four-point (0 [none] to 3 [severe]) categorical scoring scale, with the maximum score being 12, called the total nasal symptom score (TNSS). The reflective TNSS (rTNSS) requires the patient to record symptom severity over the previous 12 hours; the instantaneous TNSS (iTNSS) requires the patient to record symptom severity at the time immediately prior to the next dose. Morning and evening rTNSS scores were averaged over the treatment period and the difference in placebo in the change from baseline rTNSS was the primary efficacy variable.

Additional key secondary efficacy variables were assessed, including mean change from baseline over the entire treatment period in AM pre-dose iTNSS, mean change from baseline over the entire treatment period in daily reflective total ocular symptom score (rTOSS) (applicable to the seasonal allergic rhinitis trials only, excluding FFR20001) and the patients’ perception of overall response to therapy. The total ocular symptom score (TOSS) was calculated on the daily assessment of three ocular symptoms (itching/burning, tearing/watering, and redness) using a four-point (0 [none] to 3 [severe]) categorical scoring scale, with the maximum score being 9.

In the four seasonal allergic rhinitis trials, AVAMYS nasal spray 110 micrograms once daily significantly improved nasal symptoms (comprising rhinorrhea, nasal congestion, sneezing and nasal itching) and ocular symptoms (comprising itching/burning, tearing/watering and redness of the eyes) compared with placebo (see Table 1). The improvement was maintained over the full 24 hours after once daily administration as evaluated by AM pre-dose iTNSS (treatment effect ranged from, -0.902 to -1.898, p<0.001 across the four studies). Similar improvement was observed for AM rTNSS and PM rTNSS and AM rTOSS and PM rTOSS suggesting consistent day time and night time relief of nasal and ocular symptoms.


Table 1: Seasonal Allergic Rhinitis - primary and secondary key endpoints 
Primary Endpoint: Daily     Secondary Endpoint: Daily rTNSS                         rTOSS
LS Mean                       LS Mean
Study        Difference       p-value      Difference       p-value (95% CI)                      (95% CI)
FFR20001          -2.012         <0.001    -                - (-2.58,-1.44)
FFR30003          -0.777          0.003         -0.546          0.008 (-1.28,-0.27)                 (-0.95,-0.14)
FFR103184          -1.757         <0.001         -0.741         <0.001 (-2.28,-1.23)                 (-1.14,-0.34)
FFR104861          -1.473         <0.001         -0.600          0.004 (-2.01,-0.94)                 (-1.01,-0.19) rTNSS = reflective Total Nasal Symptom Scores (comprising rhinorrhea, nasal congestion, sneezing and nasal itching);
rTOSS = reflective Total Ocular Symptom Scores (comprising itching/burning, tearing/watering and redness of the eyes);
LS = Least square; LS Mean Difference = LS mean change from baseline in active – LS mean change from baseline in placebo;
CI = Confidence interval

Onset of action was experienced as early as eight hours after initial administration.
Significant improvement in symptoms was observed in the first 24 hours in all studies, and continued to improve over several days.

AVAMYS nasal spray significantly improved the patients’ perception of overall response to therapy. Additionally, the patients’ quality of life (assessed by the Rhinoconjunctivitis Quality of Life Questionnaire – RQLQ), was significantly improved from baseline with AVAMYS nasal spray compared to placebo (Minimum Important 
Difference in all studies = improvement of at least -0.5 over placebo; treatment difference ranged from -0.572 to - 1.000, p<0.001, across the four studies).

In the perennial allergic rhinitis trial, AVAMYS nasal spray 110 micrograms once daily significantly improved nasal symptoms compared to placebo (mean change from baseline in daily rTNSS, LS mean difference = -0.706, p=0.005, 95%CI -1.20,-0.21).
The improvement in nasal symptoms was maintained over the full 24 hours after once daily administration. The patients’ perception of overall response to therapy was significantly improved compared to placebo. Although numerical improvements in overall RQLQ scores with AVAMYS nasal spray 110 microgram were noted, these were not statistically significant when compared to placebo.

In a two-year study designed to assess the ocular safety of AVAMYS (110 micrograms once daily intranasal spray), adults and adolescents with perennial allergic rhinitis received either AVAMYS nasal spray (n=367) or placebo (n=181). The primary outcomes [time to increase in posterior subcapsular opacity (≥0.3 units from baseline in Lens Opacities Classification System, Version III (LOCS III grade, a visual comparison classification system)) and time to increase in intraocular pressure (IOP; ≥7 mmHg from baseline)] were not statistically significant between the two groups.
Increases in posterior subcapsular opacity (≥0.3 units from baseline) were more frequent in subjects treated with AVAMYS nasal spray 110 micrograms [14 (4%)] versus placebo [4 (2%)] and were transient in nature for ten subjects in the AVAMYS nasal spray group and two subjects in the placebo group. Increases in IOP (≥7 mmHg from baseline) were more frequent in subjects treated with AVAMYS nasal spray 110 micrograms: 7 (2%) for AVAMYS nasal spray 110 micrograms once daily and 1 (<1%) for placebo. These events were transient in nature for four subjects in the AVAMYS nasal spray group and one placebo subject; for two additional subjects in the fluticasone furoate group the finding occurred at the final visit and it could not be determined whether the event was transient or not. At weeks 52 and 104, 95% of subjects in both treatment groups had posterior subcapsular opacity values within ± 0.1 of baseline values for each eye and, at week 104, ≤1% of subjects in both treatment groups had ≥0.3 increase from baseline in posterior subcapsular opacity. At weeks 52 and 104, the majority of subjects (>95%) had IOP values of within ± 5mmHg of the baseline value. Increases in posterior subcapsular opacity or IOP were not accompanied by any adverse events of cataracts or glaucoma.

Seasonal and Perennial Allergic Rhinitis in Children (2 to 11 years of age) 
The paediatric dose is based on assessment of the efficacy data across the allergic rhinitis population in children.
Two randomised, double blind, parallel group, placebo-controlled trials have investigated the safety and efficacy of AVAMYS nasal spray 55 micrograms and 110 micrograms once daily in the treatment of children 2 to <12 years of age with 
symptoms of seasonal or perennial allergic rhinitis.
In the seasonal allergic rhinitis trial (FFR100010) of two weeks duration, AVAMYS nasal spray 110 micrograms once daily was effective on primary (daily rTNSS, LS mean difference = -0.616, p=0.025, 95%CI -1.15,-0.08) and all secondary nasal endpoints, except the individual reflective score for rhinorrhea. No significant differences were observed between AVAMYS nasal spray 55 micrograms and placebo on any endpoint.
In the perennial allergic rhinitis trial (FFR30008) of twelve weeks duration, with the primary endpoint assessed over the first 4 weeks, AVAMYS nasal spray 55 micrograms once daily was effective on daily rTNSS (LS mean difference = -0.754, p=0.003, 95%CI -1.24,-0.27).
Although there was a trend towards improvement in rTNSS with AVAMYS nasal spray 110 micrograms this did not reach statistical significance (LS mean difference = - 0.452, p=0.073, 95%CI -0.95, 0.04).

The above efficacy results are based on children 6 to <12 years of age. Efficacy in children 2 to <6 years of age was supported by a numerical decrease in the rTNSS.
A randomised, double-blind, parallel-group, multicenter, one-year placebo-controlled clinical growth study (FFR101782) evaluated the effect of AVAMYS nasal spray nasal spray 110 micrograms daily on growth velocity in 474 prepubescent children (5 to 7.5 years of age for girls and 5 to 8.5 years of age for boys) with stadiometry. Mean growth velocity over the 52- week treatment period was lower in the patients receiving AVAMYS nasal spray (5.19 cm/year) compared to placebo (5.46 cm/year). The mean treatment difference was -0.27 cm per year [95% CI -0.48 to -0.06].

At baseline, mean daily 24-h rTNSS as reported by subjects in the placebo group was similar to rTNSS reported by the AVAMYS nasal spray group (6.099 and 6.118, respectively). Daily 24-h rTNSS decreased in both the placebo and AVAMYS nasal spray groups over 1-52 weeks of treatment. This reduction in nasal symptom scores was consistently equal or greater for the AVAMYS nasal spray treated group (mean change from baseline -1.23) over treatment weeks 1-52 compared with the placebo treated group (mean change from baseline –0.99). Study treatment compliance based on daily e-diary recordings was high and similar between the treatment groups, and was supported by changes in nasal spray device weights.

These findings may have been due to several factors including the naturally occurring increase and decrease in frequency and severity of the symptoms of PAR; the subjective nature of symptom ratings; variations in the maturity of the patients; the need for parental assistance in rating symptoms; and the availability of the study supplied loratadine syrup.
Mean loratadine syrup rescue medication use was approximately 0.5 teaspoon per day for both treatment groups over the 52 week treatment period. There was little change from baseline in the percentage of rescue-free days for both treatment groups (-2.23%, 
placebo; - 2.96%, AVAMYS nasal spray).

Pharmacokinetic Properties

5.2 PHARMACOKINETIC PROPERTIES
Absorption
Fluticasone furoate undergoes extensive first-pass metabolism and incomplete absorption in the liver and gut resulting in negligible systemic exposure. The intranasal dosing of 110 micrograms once daily does not typically result in measurable plasma concentrations (<10 picograms/mL). Fluticasone furoate has a low (0.50%) systemic bioavailability at intranasal doses of up to 2640 micrograms per day.
Distribution
The plasma protein binding of fluticasone furoate is greater than 99%. Fluticasone furoate is widely distributed with volume of distribution at steady-state of, on average, 608 L.
Metabolism
Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7L/h) from systemic circulation principally by hepatic metabolism to an inactive 17beta-carboxylic metabolite, by the cytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17beta-carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.
Excretion
Elimination was primarily via the faecal route following oral and intravenous administration indicative of excretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively.
Special patient populations
Elderly
Only a small number of elderly subjects (n=23/872; 2.6%) provided pharmacokinetic data.
There was no evidence for a higher incidence of subjects with quantifiable fluticasone furoate concentrations in the elderly, when compared to the younger subjects.
Children
Fluticasone furoate is typically not quantifiable (<10 picograms/mL) following intranasal dosing of 110 micrograms once daily. Quantifiable levels were observed in <16% of paediatric patients following intranasal dosing of 110 micrograms once daily and only <7% of paediatric patients following 55 micrograms once daily. There was no evidence 
for a higher incidence of quantifiable levels of fluticasone furoate in younger children (less than 6 years of age).
Renal impairment
Fluticasone furoate is not detectable in urine from healthy volunteers after intranasal dosing. Less than 1% of dose-related material is excreted in urine and therefore renal impairment would not be expected to affect the pharmacokinetics of fluticasone furoate.
Hepatic impairment
There are no data on intranasal fluticasone furoate in subjects with hepatic impairment. Data are available following inhaled administration of fluticasone furoate (as fluticasone furoate or fluticasone furoate/vilanterol) to subjects with hepatic impairment that are also applicable for intranasal dosing. A study of a single 400 microgram dose of oral inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh B) resulted in increased Cmax
(42%) and AUC(0-∞) (172%) compared to healthy subjects. Following repeat dosing of orally inhaled fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (up to 3-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 (fluticasone furoate/vilanterol 200/25 micrograms) in subjects with moderate hepatic impairment (Child-Pugh B) was associated with an average
34% reduction in serum cortisol compared with healthy subjects. In subjects with severe hepatic impairment (Child-Pugh C) that received a lower dose of 100/12.5 micrograms there was no reduction in serum cortisol. Based on these findings the average predicted exposure for 110 micrograms of intranasal fluticasone furoate in this patient population would not be expected to result in clinically significant suppression of cortisol.