Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics including triple combinations with corticosteroids, ATC code: R03AL11 
Mechanism of action

Trixeo Aerosphere contains budesonide, a glucocorticosteroid, and two bronchodilators: glycopyrronium, a long-acting muscarinic antagonist (anticholinergic) and formoterol, a long-acting β2-adrenergic agonist.

Budesonide is a glucocorticosteroid which when inhaled has a rapid (within hours) and dose dependent anti-inflammatory action in the airways.


Glycopyrronium is a long-acting, muscarinic antagonist, which is often referred to as an anticholinergic. The major targets for anticholinergic drugs are muscarinic receptors located in the respiratory tract. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. Antagonism is competitive and reversible.
Prevention of methylcholine and acetylcholine-induced bronchoconstrictive effects was dose- dependent and lasted more than 12 hours.

Formoterol is a selective β2-adrenergic agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose dependent, with an onset of effect within 1-3 minutes after inhalation.
The duration of effect is at least 12 hours after a single dose.

Clinical efficacy

The efficacy and safety of Trixeo Aerosphere was evaluated in patients with moderate to very severe COPD in two randomised, parallel-group trials, ETHOS and KRONOS. Both studies were multicentre, double-blind studies. Patients were symptomatic with a COPD Assessment Test (CAT) score ≥10 while receiving two or more daily maintenance therapies for at least 6 weeks prior to screening.

ETHOS was a 52-week trial (N=8,588 randomised; 60% male, mean age of 65) that compared two inhalations twice daily of Trixeo Aerosphere, formoterol fumarate dihydrate/glycopyrronium (FOR/GLY) MDI 5/7.2 micrograms, and formoterol fumarate dihydrate/budesonide (FOR/BUD) MDI 5/160 micrograms. Patients had moderate to very severe COPD (post-bronchodilator FEV1 ≥25% to <65% predicted) and were required to have a history of one or more moderate or severe COPD exacerbations in the year prior to screening. The proportion of patients with moderate, severe and very severe COPD was 29%, 61% and 11% respectively. The mean baseline FEV1 across all groups was 1,021-1,066 mL, and during screening the mean post-bronchodilator percent predicted FEV1 was 43% and mean CAT score was 19.6. The primary endpoint of the ETHOS trial was the rate of on-treatment moderate or severe COPD exacerbations for Trixeo Aerosphere compared with FOR/GLY MDI and FOR/BUD MDI.

KRONOS was a 24-week trial (N=1,902 randomised; 71% male, mean age of 65) that compared two inhalations twice daily of Trixeo Aerosphere, FOR/GLY MDI 5/7.2 micrograms, FOR/BUD MDI 5/160 micrograms and open-label active comparator formoterol fumarate dihydrate/budesonide Turbuhaler (FOR/BUD TBH) 6/200 micrograms. Patients had moderate to very severe COPD (post- bronchodilator FEV1 ≥25% to <80% predicted). The proportion of patients with moderate, severe and very severe COPD was 49%, 43% and 8% respectively. The mean baseline FEV1 across all groups was 1,050-1,193 mL, and during screening the mean post-bronchodilator percent predicted FEV1 was 50%, over 26% of patients reported a history of one or more moderate or severe COPD exacerbation in the past year and the mean CAT score was 18.3. There was a 28-week extension, for up to 52 weeks of treatment, in a subset of subjects. The primary endpoints of the KRONOS trial were the on- treatment FEV1 area under the curve from 0-4 hours (FEV1 AUC0-4) over 24 weeks for Trixeo Aerosphere compared to FOR/BUD MDI and the on-treatment change from baseline in morning pre- dose trough FEV1 over 24 weeks for Trixeo Aerosphere compared to FOR/GLY MDI.

At study entry, the most common COPD medications reported in the ETHOS and KRONOS studies were ICS+LABA+LAMA (39%, 27% respectively), ICS+LABA (31%, 38% respectively) and LAMA+LABA (14%, 20% respectively).

Effect on exacerbations

Moderate or severe exacerbations:
In the 52-week ETHOS study, Trixeo Aerosphere significantly reduced the annual rate of on-treatment moderate/severe exacerbations by 24% (95% CI: 17, 31; p<0.0001) compared with FOR/GLY MDI (rate; 1.08 vs 1.42 events per patient year) and by 13% (95% CI: 5, 21; p=0.0027) compared with FOR/BUD MDI (rate; 1.08 vs 1.24 events per patient year).

The benefits observed on annualised rate of moderate/severe COPD exacerbations over 24 weeks in KRONOS were generally consistent with those observed in ETHOS. Improvements compared with FOR/GLY MDI were statistically significant; however improvements compared with FOR/BUD MDI and FOR/BUD TBH did not reach statistical significance.

Severe exacerbations (resulting in hospitalisation or death):
In ETHOS, Trixeo Aerosphere numerically reduced the annual rate of on-treatment severe exacerbations by 16% (95% CI: -3, 31; p=0.0944) compared with FOR/GLY MDI (rate; 0.13 vs 0.15 events per patient year) and significantly reduced the annual rate of on-treatment severe exacerbations by 20% (95% CI: 3, 34; p=0.0221) compared with FOR/BUD MDI (rate; 0.13 vs 0.16 events per patient year).

In both studies, benefits on exacerbations were observed in patients with moderate, severe and very severe COPD.

Effects on lung function

In ETHOS and KRONOS, Trixeo Aerosphere improved on-treatment lung function (FEV1) compared with FOR/GLY MDI and FOR/BUD MDI (see Table 2 for ETHOS and Table 3 for KRONOS). There was a sustained effect over the 24-week treatment period in both studies, and over 52 weeks in ETHOS.

Table 2: Lung function analyses – ETHOS (spirometric sub-study)
Trixeo      FOR/GLY   FOR/BUD             Treatment difference
Aerosphere        MDI       MDI                    95% CI
(N=747)       (N=779)   (N=755)         Trixeo              Trixeo
Aerosphere vs.     Aerosphere vs.
FOR/GLY MDI       FOR/BUD MDI
Trough FEV1 (mL)   129 (6.5)      86 (6.6)   53 (6.5)        43 mL              76 mL over 24 weeks, LS                                           (25, 60)           (58, 94) mean change from                                           p<0.0001           p<0.0001# baseline (SE)
FEV1 AUC0-4 over      294 (6.3)        245 (6.3)     194 (6.3)           49 mL                  99 mL 24 weeks; LS mean                                                       (31, 66)               (82, 117) change from                                                            p<0.0001#               p<0.0001 baseline (SE)
# p-value not adjusted for multiplicity in hierarchical testing plan
LS = least squares, SE = standard error, CI = confidence intervals, N = number in Intent-to-Treat population

Table 3: Lung function analyses – KRONOS
Trixeo     FOR/     FOR/               FOR/                 Treatment difference Aero-       GLY     BUD                BUD                        95% CI sphere     MDI      MDI                TBH           Trixeo        Trixeo        Trixeo (N=639)   (N=625)     (N=314)     (N=318)      Aerosphere Aerosphere Aerosphere vs. FOR/GLY     vs. FOR/BUD     vs. FOR/BUD
MDI             MDI             TBH
Trough FEV1           147       125       73 (9.2)    88 (9.1)       22 mL           74 mL           59 mL (mL) over 24         (6.5)     (6.6)                                 (4, 39)        (52, 95)        (38, 80) weeks, LS mean                                                      p=0.0139       p<0.0001        p<0.0001# change from baseline (SE)
FEV1 AUC0-4           305       288         201            214       16 mL          104 mL           91 mL over 24 weeks;       (8.4)     (8.5)       (11.7)         (11.5)    (-6, 38)       (77, 131)        (64, 117) LS mean change                                                     p=0.1448#       p<0.0001         p<0.0001 

from baseline
(SE)
# p-value not adjusted for multiplicity in hierarchical testing plan
LS = least squares, SE = standard error, CI = confidence intervals, N = number in Intent-to-Treat population

Symptom relief

In ETHOS, the baseline average dyspnoea scores ranged from 5.8 – 5.9 across the treatment groups.
Trixeo Aerosphere significantly improved breathlessness (measured using the Transition Dyspnoea Index (TDI) focal score over 24 weeks) compared with FOR/GLY MDI (0.40 units; 95% CI: 0.24, 0.55; p<0.0001) and compared with FOR/BUD MDI (0.31 units; 95% CI: 0.15, 0.46; p<0.0001).
Improvements were sustained over 52 weeks. In KRONOS, the baseline average dyspnoea scores ranged from 6.3 – 6.5 across the treatment groups. Trixeo Aerosphere significantly improved breathlessness over 24 weeks compared with FOR/BUD TBH (0.46 units; 95% CI: 0.16, 0.77; p=0.0031). Improvements compared with FOR/GLY MDI, and FOR/BUD MDI did not reach statistical significance.

Health-related quality of life

In ETHOS, Trixeo Aerosphere significantly improved disease-specific health status (as assessed by the St. George’s Respiratory Questionnaire [SGRQ] total score) over 24 weeks compared with FOR/GLY MDI (improvement -1.62; 95% CI: -2.27, -0.97; p<0.0001) and compared with FOR/BUD MDI (improvement -1.38, 95% CI: -2.02, -0.73; p<0.0001). Improvements were sustained over 52 weeks. In KRONOS, improvements compared with FOR/GLY MDI, FOR/BUD MDI and FOR/BUD TBH did not reach statistical significance.

Use of rescue medication

In ETHOS, Trixeo Aerosphere significantly reduced the on-treatment use of rescue medication over 24 weeks compared with FOR/GLY MDI (treatment difference -0.51 puffs/day; 95% CI: -0.68, -0.34;
p<0.0001) and FOR/BUD MDI (treatment difference -0.37 puffs/day; 95% CI: -0.54, -0.20; p<0.0001). Reductions were sustained over 52 weeks. In KRONOS, differences compared with FOR/GLY MDI, FOR/BUD MDI and FOR/BUD TBH were not statistically significant.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Following inhalation of the formoterol, glycopyrronium and budesonide combination, the pharmacokinetics of each component was similar to those observed when each active substance was administered separately.

Effect of a spacer
The use of this medicinal product with the Aerochamber Plus Flow-Vu spacer in healthy volunteers increased the total systemic exposure (as measured by AUC0-t) to budesonide and glycopyrronium by 33% and 55%, respectively, while exposure to formoterol was unchanged. In patients with good inhalation technique, systemic exposure was not increased with the use of a spacer.

Absorption

Budesonide


Following inhaled administration of this medicinal product in subjects with COPD, budesonide Cmax occurred within 20 to 40 minutes. Steady state is achieved after approximately 1 day of repeated dosing of this medicinal product and the extent of exposure is approximately 1.3 times higher than after the first dose.

Glycopyrronium
Following inhaled administration of this medicinal product in subjects with COPD, glycopyrronium Cmax occurred at 6 minutes. Steady state is achieved after approximately 3 days of repeated dosing of this medicinal product and the extent of exposure is approximately 1.8 times higher than after the first dose.

Formoterol
Following inhaled administration of this medicinal product in subjects with COPD, formoterol Cmax occurred within 40 to 60 minutes. Steady state is achieved after approximately 2 days of repeated dosing with this medicinal product and the extent of exposure is approximately 1.4 times higher than after the first dose.

Distribution

Budesonide
The estimated budesonide apparent volume of distribution at steady-state is 1200 L, via population pharmacokinetic analysis. Plasma protein binding is approximately 90% for budesonide.

Glycopyrronium
The estimated glycopyrronium apparent volume of distribution at steady-state is 5500 L, via population pharmacokinetic analysis. Over the concentration range of 2-500 nmol/L, plasma protein binding of glycopyrronium ranged from 43% to 54%.

Formoterol
The estimated formoterol apparent volume of distribution at steady-state is 2400 L, via population pharmacokinetic analysis. Over the concentration range of 10-500 nmol/L, plasma protein binding of formoterol ranged from 46% to 58%.

Biotransformation

Budesonide
Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6 β-hydroxy-budesonide and 16-hydroxy-prednisolone, is less than 1% of that of budesonide.

Glycopyrronium
Based on literature, and an in-vitro human hepatocyte study, metabolism plays a minor role in the overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in the metabolism of glycopyrronium.

Formoterol
The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation.

Elimination

Budesonide
Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are excreted in urine as such or in conjugated form. Only negligible amounts of 
unchanged budesonide have been detected in the urine. The effective terminal elimination half-life of budesonide derived via population pharmacokinetic analysis was 5 hours.

Glycopyrronium
After IV administration of a 0.2 mg dose of radiolabelled glycopyrronium, 85% of the dose was recovered in urine 48 hours post dose and some of radioactivity was also recovered in bile. The effective terminal elimination half-life of glycopyrronium derived via population pharmacokinetic analysis was 15 hours.

Formoterol
The excretion of formoterol was studied in six healthy subjects following simultaneous administration of radiolabelled formoterol via the oral and IV routes. In that study, 62% of the drug related radioactivity was excreted in the urine while 24% was eliminated in the faeces. The effective terminal elimination half-life of formoterol derived via population pharmacokinetic analysis was 10 hours.

Special populations

Age, gender, race/ethnicity and weight
Dose adjustments are not necessary based on the effect of age, gender or weight on the pharmacokinetic parameters of budesonide, glycopyrronium and formoterol. There were no major differences in total systemic exposure (AUC) for all compounds between healthy Japanese, Chinese and Western subjects. Insufficient pharmacokinetic data is available for other ethnicities or races.

Hepatic impairment
No pharmacokinetic studies have been performed with this medicinal product in patients with hepatic impairment. However, because both budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver impairment.
Glycopyrronium is primarily cleared from the systemic circulation by renal excretion and hepatic impairment would therefore not be expected to affect systemic exposure.

Renal impairment
Studies evaluating the effect of renal impairment on the pharmacokinetics of budesonide, glycopyrronium and formoterol were not conducted.

The effect of renal impairment on the exposure to budesonide, glycopyrronium and formoterol for up to 24 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) varied from 31-192 mL/min representing a range of moderate to no renal impairment.
Simulation of the systemic exposure (AUC0-12) in subjects with COPD with moderate renal impairment (eGFR of 45 mL/min) indicates an approximate 68% increase for glycopyrronium compared to subjects with COPD with normal renal function (eGFR of >90 mL/min). Renal function was found not to affect exposure to budesonide or formoterol. Subjects with COPD with both low body weight and moderate-severe impaired renal function may have an approximate doubling of systemic exposure to glycopyrronium.