Bretaris Genuair

Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also called anticholinergic), with a longer binding time to Mz receptors than to M2 receptors. Mo - receptors serve as mediators in the reduction of smooth muscles of the respiratory tract. Inhaled aclidinium bromide acts locally in the lungs, as an antagonist of the M3 - receptors of the smooth muscles of the respiratory tract and causes expansion of the bronchi. In vitro and in vivo preclinical studies have demonstrated rapid, dose-dependent and long-term inhibition of aclidinium by bronchospasm bromide caused by acetylcholine. Aclidinium bromide is rapidly destroyed in plasma, so the number of systemic anticholinergic side effects is low.

Pharmacodynamic action

Clinical efficacy studies have shown that Bretaris Jenweir 'provides a clinically significant improvement in lung function (measured by forced expiratory volume in one second [FEV1]) for more than 12 hours after morning and evening dosing, which occurred 30 minutes after taking the first dose (increase FEV1 compared with the initial level of 124-133 ml). Maximum bronchodilation was achieved within 1-3 hours after administration of the dose with an average peak of FEV1 improvements in relation to the initial level of 227-268 ml in equilibrium.

Electrophysiology of the heart

When prescribing aclidinium bromide (200 mcg or 800 mcg), healthy volunteers once a day for 3 days had no effect on the QT interval (corrected by the method of Friederitia or Bazetta or individually).

There was also no clinically significant effect of Bretaris 'Dzhenueyr' on heart rate during 24-hour Holter monitoring in 336 patients (164 of whom received Bretaris Dzhenueyri® twice a day at a dose of 322 μg) after 3 months of use.

Clinical efficacy

The phase III clinical research program of Bretaris® Dzhenueyr® included 269 patients treated with Bretaris® Dzhenueyr® at a dose of 322 mcg twice a day during one 6-month randomized study with placebo control, and 190 patients treated with Betharis® Dzhenueyr ® at a dose of 322 mcg twice a day during another 3-month, randomized, placebo-controlled trial. Efficacy was assessed by the dynamics of lung function and clinical symptoms, such as shortness of breath, the health status determined by the diagnosis, the use of emergency drugs and the presence of exacerbations. In conducting long-term safety studies, Bretaris® Dzhenueyri® demonstrated bronchodilation efficacy with a duration of use of more than 1 year.

Bronchodilation

When conducting a 6-month study, patients who received Bretaris® Dzhenueir® at a dose of 322 mcg twice a day had a clinically significant improvement in lung function (measured with FEV]). The maximum bronchodilation effect was manifested from the first day and persisted for a 6-month period of application therapy. After 6 months of therapy, the average improvement before taking the morning dose (minimum) of FEV] compared with placebo was 128 ml (95% CI = 85-170; p

Similar observations were made for Bretaris® Dzhenueyri® during the 3-month study.

Disease-specific health and symptomatic improvement

Bretaris® Dzhenueyri® provided a clinically significant improvement in dyspnea (assessed using the transient dyspnea index [TDI]) and health condition associated with the disease (assessed using the St. George Respiratory Survey [SGRQ]). The table below shows the reduction of symptoms after 6 months of use of Bretaris® Jenewair®.

Variable	Treatment		Improvement compared with placebo	Value R
	Bretaris * „_ „„ ® Placebo Jenwair
Transient dyspnea index
Percentage of patients with minimal clinically important difference3	56,9	45,5	1.68-fold boost probabilities	0,004
Mean change from baseline	1,9	0,9	1.0 unit
Respiratory Questionnaire at St. George's Hospital
Percentage of patients with minimal clinically important difference	57,3	41,0	1.87-fold boost probabilities
Mean change from baseline	-7.4	-2,8	- 4.6 units

a) The minimum clinically important difference (MCID) is at least 1 unit of change in the Transient Dyspnea Index.

b) The minimum clinically important difference (MCID) is at least 4 units of change according to the Respiratory Questionnaire of St. George's Hospital.

c) The odds ratio, the increased likelihood of achieving the Minimum clinically important difference compared to placebo.

Patients who received Bretaris® Dzhenueyr® required fewer emergency treatment drugs than patients who received placebo (a decrease of 0.95 administrations per day for 6 months [p = 0.005]). Bretaris® Dzhenueyr® also improved the daytime symptoms of COPD (shortness of breath, cough and sputum formation), as well as night and early morning clinical symptoms.

A pool analysis of the effectiveness of 6-month and 3-month placebo-controlled studies demonstrated a significant decrease in the incidence of moderate and severe exacerbations (requiring antibiotic therapy or glucocorticosteroid therapy or leading to hospitalization) with 322 mcg of aclidinium twice a day compared with placebo (patient frequency per year: 0.31 versus 0.44, respectively; p = 0.0149).

Exercise tolerance

A 3-week, randomized, cross-sectional clinical trial with placebo-controlled treatment with Bretaris® Dzhenueyr® showed a statistically significant increase in exercise duration by 58 seconds compared to placebo (95% CI = 9-108; p = 0.021; values ​​before therapy: 486 seconds).

When Bretaris® Dzhenueir® was used, there was a statistically significant decrease in excessive overstretching of the lungs at rest (functional residual capacity [IEF] = 0.197 l [95% CI = 0.321, 0.072; p = 0.002]; residual volume [RV] = 0.238 l [95 % CI = 0.396, 0.079; p =: 0.004]), and an improvement in the minimum inhalation capacity was observed (by 0.078 l; 95% CI = 0.01, 0.145; p = 0.025) and a decrease in shortness of breath when performing exercises (Borg scale) (by 0.63 Borg units; 95% CI = 1.11, 0.14; p = 0.012).

Suction

Aclidinium bromide is rapidly absorbed from the lungs, reaching a maximum plasma concentration within 5 minutes after inhalation in healthy volunteers, and usually during the first 15 minutes in patients with COPD. The fraction of the inhaled dose that reached the systemic circulation as unchanged aclidinium is very low, less than 5%.

The maximum plasma concentration achieved after inhalation of a dry powder in patients with COPD with a single dose of 400 μg of aclidinium bromide was approximately 80 pg / ml. Equilibrium plasma concentration was reached within 7 days when taken twice a day and, given the short half-life, the equilibrium concentration can be reached soon after taking the first dose. Accumulation when re-taking at the equilibrium level of concentrations was not observed.

Distribution

The total amount of bromide delivered to the lungs via the Bretaris Jenewair Aclidinium inhaler was approximately 30% of the metered dose.

The binding of aclidinium bromide to plasma proteins in vitro most likely corresponds to the binding of metabolites to proteins, due to the rapid hydrolysis of plasma aclidinium bromide, the binding to plasma proteins was 87% for carboxylic acid metabolite and 15% for alcohol metabolite. The main plasma protein that binds aclidinium bromide is albumin.

Biotrapsformation

Aclidinium bromide is rapidly and actively hydrolyzed to its pharmacologically inactive alcohol derivatives and carboxylic acid derivatives. There is a chemical hydrolysis (non-enzymatic), and enzymatic, with the participation of esterases. The major esterase involved in human hydrolysis is butyrylcholinesterase. The level of the acid metabolite in the blood plasma after inhalation is about 100 times higher than the level of the alcohol metabolite and the unchanged active substance.

Low absolute bioavailability of aclidinium bromide with inhalation (

Biotransformation with the participation of cytochrome P450 isoenzymes (CYP450) plays a minor role in the overall metabolic clearance of aclidinium bromide.

In vitro tests showed that aclidinium bromide at a therapeutic dose or its metabolites do not inhibit or induce any isoenzymes of cytochrome P450 (CYP450) and do not inhibit the activity of esterases (carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro tests have shown that aclidinium bromide or its metabolites are not substrates or inhibitors of P-glycoprotein.

Removal

The final period and the absorption of aclidinium bromide is about 2-3 hours.

After intravenous administration to healthy volunteers, 400 mcg of radiolabeled aclidinium bromide, about 1% of the dose was excreted unchanged in the urine.

Up to 65% of the dose was excreted in the form of metabolites in the urine and up to 33% in the form of metabolites with feces.

After inhalation administration to healthy volunteers and patients with COPD 200 mcg and 400 mcg of aclidinium bromide, a very small amount, about 0.1% of the dose taken, was excreted unchanged in the urine, which indicates that renal clearance plays a minor role in the overall clearance of aclidinium from blood plasma.

Linearity / nonlinearity

Aclidinium bromide in the therapeutic range has a linear and time-independent pharmacokinetics.

Pharmacokinetic / pharmacodynamic ratio

Given that aclidinium bromide has a local effect in the lungs and is rapidly destroyed in plasma, there is no direct correlation between pharmacokinetics and pharmacodynamics.

Special patient groups

Elderly patients

The pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD are similar in patients aged 40–59 years and in patients aged 70 and older. Therefore, in elderly patients with COPD, dose adjustment is not required.

Patients with impaired liver function

In patients with impaired liver function tests were not conducted. Since aclidinium bromide is metabolized mainly by chemical and enzymatic cleavage in plasma, it is very unlikely that an abnormal liver function changes its systemic effect. In patients with COPD and abnormal liver function, dose adjustment is not required.

Patients with impaired renal function

In patients with normal renal function and with its violation, no significant differences in pharmacokinetics were found. Therefore, in patients with COPD and renal dysfunction, dose adjustment and additional monitoring is not required.