Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic Properties

Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti- inflammatory action within the lungs resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.

Fluticasone propionate containing medications in asthma during pregnancy 
An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure to inhaled FP alone and salmeterol-FP combination relative to non-FP containing ICS. No placebo comparator was included in this study.

Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies, 131 diagnosed MCMs were identified; 1612 (30%) were exposed to FP or salmeterol-FP of which 42 diagnosed MCMs were identified.
The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5 – 2.3) for FP exposed vs non- FP ICS exposed women with moderate asthma and 1.2 (95%CI: 0.7 – 2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was identified following first trimester exposure to FP alone versus salmeterol-FP combination. Absolute risks of MCM across the asthma severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies which is comparable to results from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research Database (2.8 MCM events per 100 pregnancies).

COPD clinical trials

TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500 mcg bd, salmeterol Diskus 50 mcg bd, fluticasone propionate (FP) Diskus 500 mcg bd or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (pre-bronchodilator) FEV1 <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all cause mortality at 3 years for Seretide vs Placebo.


Seretide
Placebo       Salmeterol 50     FP 500
50/500
N = 1524      N = 1521          N = 1534
N = 1533
All cause mortality at 3 years
Number of deaths        231            205                 246               193 (%)                     (15.2%)        (13.5%)             (16.0%)           (12.6%) Hazard Ratio vs                        0.879               1.060             0.825 Placebo (CIs)           N/A            (0.73, 1.06)        (0.89, 1.27)      (0.68, 1.00) p value                                0.180               0.525             0.0521 Hazard Ratio
0.932               0.774
Seretide 50/500 vs
N/A            (0.77, 1.13)        (0.64, 0.93)      N/A components (CIs)
0.481               0.007 p value
1. Non significant P value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status
There was a trend towards improved survival in subjects treated with Seretide compared with placebo over 3 years however this did not achieve the statistical significance level p≤0.05.

The mean number of moderate to severe exacerbations per year was significantly reduced with Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.

Health Related Quality of Life, as measured by the St George’s Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for Seretide compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was -1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.

The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for Seretide (Hazard ratio for Seretide vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

Pharmacokinetic Properties

5.2 Pharmacokinetic Properties

The absolute bioavailability of fluticasone propionate for each of the available inhaler devices has been estimated from within and between study comparisons of inhaled and intravenous pharmacokinetic data. In healthy adult subjects the absolute bioavailability has been estimated for fluticasone propionate Accuhaler/Diskus (7.8%), fluticasone propionate Diskhaler (9.0%) and fluticasone propionate Inhaler (10.9%) respectively. In patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed.

Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear 

increase in systemic exposure with increasing inhaled dose.
The disposition of fluticasone propionate is characterised by high plasma clearance (1150 ml/min), a large volume of distribution at steady-state (approximately 300 l) and a terminal half-life of approximately 8 hours.

Plasma protein binding is 91%.

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.

The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug.