Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties
Pharmacotherapeutic Group: Selective β2-adrenoreceptor agonists.

ATC Code:            R03AC12

Salmeterol is a selective long-acting (usually 12 hours) β2-adrenoceptor agonist with a long side-chain which binds to the exo-site of the receptor. These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilatation, lasting for at least 12 hours, than recommended doses of conventional short-acting β2-agonists. In vitro tests have shown that salmeterol is a potent and long-lasting inhibitor of the release from the human lung of mast cell mediators, such as histamine, leukotrienes and prostaglandin D2. In man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids, which should not be stopped or reduced when Serevent Diskus is prescribed.

Salmeterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function, and quality of life. Salmeterol acts as a β2-agonist on the reversible component of the disease. In vitro salmeterol has also been shown to increase cilial beat frequency of human bronchial epithelial cells, and also reduce a ciliotoxic effect of Pseudomonas toxin on the bronchial epithelium of patients with cystic fibrosis.

Asthma Clinical Trials

The Salmeterol Multi-centre Asthma Research Trial (SMART)
SMART was a multi-centre, randomised, double-blind, placebo-controlled, parallel group 28- week study in the US which randomised 13,176 patients to salmeterol (50μg twice daily) and 13,179 patients to placebo in addition to the patients’ usual asthma therapy. Patients were enrolled if ≥12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences.

Key findings from SMART: primary endpoint
Patient group              Number of primary endpoint Relative Risk events /number of patients (95% salmeterol        placebo  confidence intervals)
All patients                   50/13,176        36/13,179         1.40 (0.91, 2.14) Patients       using   inhaled 23/6,127         19/6,138          1.21 (0.66, 2.23) steroids
Patients not using inhaled 27/7,049             17/7,041          1.60 (0.87, 2.93) steroids

African-American patients         20/2,366         5/2,319             4.10       (1.54, 10.90)
(Risk in bold is statistically significant at the 95% level.)

Key findings from SMART by inhaled steroid use at baseline: secondary endpoints Number of secondary Relative Risk endpoint           events (95%        confidence
/number of patients         intervals) salmeterol placebo
Respiratory -related death
Patients using inhaled steroids        10/6127      5/6138          2.01 (0.69, 5.86) Patients not using inhaled steroids    14/7049      6/7041          2.28 (0.88, 5.94) Combined asthma-related death or life-threatening experience
Patients using inhaled steroids        16/6127      13/6138         1.24 (0.60, 2.58) Patients not using inhaled steroids    21/7049      9/7041          2.39 (1.10, 5.22) Asthma-related death
Patients using inhaled steroids        4/6127       3/6138          1.35 (0.30, 6.04) Patients not using inhaled steroids 9/7049           0/7041        *
(*=could not be calculated because of no events in placebo group. Risk in bold is statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all- cause death or life-threatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population.

COPD clinical trials

TORCH study
TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500mcg bd, salmeterol Diskus 50mcg bd, fluticasone propionate (FP) Diskus 500mcg 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.

Salmeterol                          Seretide
Placebo                           FP 500
50                                  50/500
N = 1524                          N = 1534
N = 1521                            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 percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for Seretide.

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 increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for Seretide. 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

Salmeterol acts locally in the lung, therefore plasma levels are not predictive of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma because of the 

very low plasma concentrations at therapeutic doses (approximately 200 pg/ml or less) achieved after inhaled dosing.

After regular dosing with salmeterol xinafoate, xinafoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 ng/ml. These concentrations are up to 1000-fold lower than steady state levels observed in toxicity studies. These concentrations in long term regular dosing (more than 12 months) in patients with airways obstruction, have been shown to produce no ill effects.