Overview
White or almost white finely dispersed, free-flowing powder containing no visible conglomerates or foreign particles.
Pharmacotherapeutic group:
ATX 340/12 R03BB05
Pharmacological properties
Pharmacodynamics
Aklidinia bromide is a competitive, selective antagonist of muscarinic receptors (also called anticholinergic), with a longer binding time to M3 receptors than to M2 receptors. M3 - receptors mediate the contraction of smooth muscles of the respiratory tract. Inhaled aclidinium bromide acts locally in the lungs, as an antagonist of M3 - smooth muscle receptors in the respiratory tract and causes bronchodilation.
Preclinical Studies in vitro and in vivo demonstrated fast, dose-dependent and long-term inhibition of aclidinium with acetylcholine-induced bronchospasm bromide. Aklidiniya bromide is rapidly destroyed in plasma, therefore, the number of systemic anticholinergic side effects is low.
Pharmacodynamic action
Clinical efficacy studies have shown that Bretaris® Genuire® provides a clinically significant improvement in lung function (as measured by forced expiratory volume in one second [FEV1]) for more than 12 hours after morning and evening intake, which occurred within 30 minutes after administration the first dose (an increase in FEV1 compared with the initial level is 124-133 ml). Maximum bronchodilation was achieved within 1-3 hours after taking a dose with an average peak of FEV1 improvements relative to the initial level of 227-268 ml in equilibrium.
When appointing Aklidinium bromide (200 mcg or 800 mcg) to healthy volunteers once a day for 3 days, no effect on the QT interval (corrected by the Friederitz or Bazetta method or individually) was observed.
There was also no clinically significant effect of Bretaris® Jenhair® on heart rate during 24-hour Holter monitoring in 336 patients (164 of which received Bretaris® Jenhair® twice a day at a dose of 322 mcg) after 3 months of use of the drug.
The Bretaris® Genuire® Phase III Clinical Trials Program included 269 patients treated with 322 mcg Bretaris® Genewair® twice daily during one 6-month, randomized, placebo-controlled study, and 190 patients treated with Bretaris® Genuire ® at a dose of 322 mcg twice daily during another 3-month, randomized, placebo-controlled study.
Efficacy was assessed by the dynamics of lung function and clinical symptoms, such as shortness of breath, according to the diagnosis of health status, the use of emergency drugs and the presence of exacerbations. In conducting long-term safety studies, Bretaris® Genuair® showed bronchodilation efficacy with a duration of use of more than 1 year.
In a 6-month study, patients receiving Bretaris® Genewair® at a dose of 322 mcg twice daily had a clinically significant improvement in lung function (measured using FEV1).
The maximum bronchodilation effect was manifested from the first day and lasted for a 6-month period of treatment. After 6 months of therapy, the average improvement before taking the morning dose (minimum) of FEV1 compared with placebo was 128 ml 340/12 CI = 85-170; p ® Genuire ® .
The pool analysis of the efficacy of 6-month and 3-month studies with placebo 340/12 showed a significant decrease in the incidence of moderate to severe exacerbations (requiring antibiotic or glucocorticosteroid therapy or leading to hospitalization) when taking 322 mcg of Aklidinium twice a day compared with placebo (frequency per patient per year: 0.31 versus 0.44, respectively; p = 0.0149). Patients who received Bretaris® Genuire® required fewer emergency drugs than patients who received placebo (with Brimica decrease complete 0.95 injections per day for 6 months [p = 0.005]). Bretaris® Genuair® also improved the daily symptoms of COPD (shortness of Brimica, coughing and sputum formation), as well as night and early morning clinical symptoms.
Exercise tolerance
During a 3-week randomized cross-sectional clinical trial with placebo control while using Bretaris® Genewair®, there was a statistically significant increase in exercise duration by 58 seconds compared with placebo (95% CI = 9-108; p = 0.021; values before therapy: 486 seconds).
When using the drug Bretaris® Genuire®, there was a statistically significant decrease in excessive lung overstretching at rest (functional residual capacity [FOE] = 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]), as well as an improvement in the minimum inspiratory capacity (by 0.078 L; 95% CI = 0.01, 0.145; p = 0.025) and a decrease in shortness of breath during exercise (Borg scale) ( by 0.63 Borg units; 95% CI = 1.11, 0.14; p = 0.012).
Pharmacokinetics
Aklidinia bromide is rapidly absorbed from the lungs, reaching a Brimica plasma concentration within 5 minutes after inhalation in healthy volunteers, and usually within the first 15 minutes in patients with COPD. The fraction of the inhaled dose that has reached systemic circulation as unchanged aklidiniya is very low, less than 5%.
The maximum plasma concentration achieved after inhalation of dry powder in patients with COPD with a single dose of 400 μg of aclidinium bromide was approximately 80 pg / ml. The equilibrium concentration in blood plasma was achieved within 7 days when taken twice a day and, given the short half-life, the equilibrium concentration can be achieved shortly after taking the first dose. Repeated intake accumulations at an equilibrium concentration level were not observed.
The total amount of aclidinium bromide that passes into the lungs through the inhaler Bretaris® Genuair® is approximately 30% of the measured dose.
The binding Brimica aclidinium bromide to plasma proteins in vitro most likely corresponds to 340/12 binding of metabolites to proteins, due to the rapid hydrolysis of aclidinium bromide in plasma, the binding to plasma proteins was 87% for a carboxylic acid metabolite and 15% for an alcohol metabolite. The main plasma protein that binds aclidinium bromide is albumin.
Aklidinia bromide is rapidly and actively hydrolyzed to its pharmacologically inactive alcohol derivatives and carboxylic acid derivatives. This list chemical hydrolysis (non-enzymatic) and enzymatic, with the participation of esterases, occur. The main esterase involved in human hydrolysis is butyrylcholinesterase. The level of acid metabolite in blood plasma after inhalation is approximately 100 times higher than the level of alcohol metabolite and unchanged active substance.
Low absolute bioavailability of aclidinium bromide by inhalation (Special patient groups
The pharmacokinetic properties of moderate to severe aclidinium bromide in patients with moderate to severe COPD are similar in patients aged 40-59 years and in patients aged 70 years and older. Therefore, in elderly patients with COPD, dose adjustment is not required.
Patients with impaired liver function
