Drugs for obstructive airway diseases, anticholinergics. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of action:
Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also known as an anticholinergic), with a longer residence time at the M3
receptors than the M2
receptors mediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs to antagonise M3
receptors of airway smooth muscle and induce bronchodilation. Nonclinical in vitro
and in vivo
studies showed rapid, dose-dependent and long-lasting inhibition by aclidinium of acetylcholine-induced bronchoconstriction. Aclidinium bromide is quickly broken down in plasma, the level of systemic anticholinergic side effects is therefore low.
Clinical efficacy studies showed that Eklira Genuair provided clinically meaningful improvements in lung function (as measured by the forced expiratory volume in 1 second [FEV1
]) over 12 hours following morning and evening administration, which were evident within 30 minutes of the first dose (increases from baseline of 124-133 mL). Maximal bronchodilation was achieved within 1-3 hours after dosing with mean peak improvements in FEV1
relative to baseline of 227-268 mL at steady-state.
No effects on QT interval (corrected using either the Fridericia or Bazett method or individually-corrected) were observed when aclidinium bromide (200 µg or 800 µg) was administered once daily for 3 days to healthy subjects in a thorough QT study.
In addition, no clinically significant effects of Eklira Genuair on cardiac rhythm were observed on 24-hour Holter monitoring after 3 months treatment of 336 patients (of whom 164 received Eklira Genuair 322 µg twice daily).
Clinical efficacy and safety:
The Eklira Genuair Phase III clinical development programme included 269 patients treated with Eklira Genuair 322 µg twice daily in one 6-month randomised, placebo-controlled study and 190 patients treated with Eklira Genuair 322 µg twice daily in one 3-month randomised, placebo-controlled study. Efficacy was assessed by measures of lung function and symptomatic outcomes such as breathlessness, disease-specific health status, use of rescue medication and occurrence of exacerbations. In the long-term safety studies, Eklira Genuair was associated with bronchodilatory efficacy when administered over a 1-year treatment period.
Bronchodilation: In the 6-month study, patients receiving Eklira Genuair 322 µg twice daily experienced a clinically meaningful improvement in their lung function (as measured by FEV1
). Maximal bronchodilatory effects were evident from day one and were maintained over the 6-month treatment period. After 6 months treatment, the mean improvement in morning pre-dose (trough) FEV1
compared to placebo was 128 mL (95% CI=85-170; p<0.0001).
Similar observations were made with Eklira Genuair in the 3 month study.
Disease-Specific Health Status and Symptomatic Benefits: Eklira Genuair provided clinically meaningful improvements in breathlessness (assessed using the Transition Dyspnoea Index [TDI]) and disease-specific health status (assessed using the St. George's Respiratory Questionnaire [SGRQ]). Table 1 shows symptom relief obtained after 6 months treatment with Eklira Genuair. (See Table 1.)
Click on icon to see table/diagram/image
Patients treated with Eklira Genuair required less rescue medication than patients treated with placebo (a reduction of 0.95 puffs per day at 6 months [p=0.005]). Eklira Genuair also improved daily symptoms of COPD (dyspnoea, cough and sputum production) and night-time and early morning symptoms.
Pooled efficacy analysis of the 6-month and 3-month placebo controlled studies demonstrated a statistically significant reduction in the rate of moderate to severe exacerbations (requiring treatment with antibiotics or corticosteroids or resulting in hospitalisations) with aclidinium 322 µg twice daily compared to placebo (rate per patient per year: 0.31 vs 0.44 respectively; p=0.0149).
Exercise tolerance: In a 3-week crossover, randomised, placebo-controlled clinical study Eklira Genuair was associated with a statistically significant improvement in exercise endurance time in comparison to placebo of 58 seconds (95% CI=9-108; p=0.021; pre-treatment value: 486 seconds). Eklira Genuair statistically significantly reduced lung hyperinflation at rest (functional residual capacity [FRC]=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 also improved trough inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and reduced dyspnoea during exercise (Borg scale) (by 0.63 Borg units; 95% CI=1.11, 0.14; p=0.012).
The European Medicines Agency has waived the obligation to submit the results of studies with Eklira Genuair in all subsets of the paediatric population in COPD (see Dosage & Administration for information on paediatric use).
Aclidinium bromide is rapidly absorbed from the lung, achieving maximum plasma concentrations within 5 minutes of inhalation in healthy subjects, and normally within the first 15 minutes in COPD patients. The fraction of the inhaled dose that reaches the systemic circulation as unchanged aclidinium is very low at less than 5%.
Steady state peak plasma concentrations achieved after dry powder inhalation by COPD patients of 400 µg aclidinium bromide were approximately 224 pg/mL. Steady-state plasma levels were attained within seven days of twice daily dosing.
Whole lung deposition of inhaled aclidinium bromide via the Genuair inhaler averaged approximately 30% of the metered dose.
The plasma protein binding of aclidinium bromide determined in vitro
most likely corresponded to the protein binding of the metabolites due to the rapid hydrolysis of aclidinium bromide in plasma; plasma protein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein that binds aclidinium bromide is albumin.
Aclidinium bromide is rapidly and extensively hydrolysed to its pharmacologically inactive alcohol- and carboxylic acid-derivatives. The hydrolysis occurs both chemically (non-enzymatically) and enzymatically by esterases, butyrylcholinesterase being the main human esterase involved in the hydrolysis. Plasma levels of the acid metabolite are approximately 100-fold greater than those of the alcohol metabolite and the unchanged active substance following inhalation.
The low absolute bioavailability of inhaled aclidinium bromide (<5%) is because aclidinium bromide undergoes extensive systemic and pre-systemic hydrolysis whether deposited in the lung or swallowed.
Biotransformation via CYP450 enzymes plays a minor role in the total metabolic clearance of aclidinium bromide.
studies have shown that aclidinium bromide at the therapeutic dose or its metabolites do not inhibit or induce any of the cytochrome P450 (CYP450) enzymes and do not inhibit esterases (carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro
studies have shown that aclidinium bromide or the metabolites of aclidinium bromide are not substrates or inhibitors of P-glycoprotein.
The terminal elimination half-life and effective half-life of aclidinium bromide are approximately 14 hours and 10 hours, respectively, following inhalation of twice daily 400 µg doses in COPD patients.
Following intravenous administration of 400 µg radiolabelled aclidinium bromide to healthy subjects, approximately 1% of the dose was excreted as unchanged aclidinium bromide in the urine. Up to 65% of the dose was eliminated as metabolites in the urine and up to 33% as metabolites in the faeces.
Following inhalation of 200 µg and 400 µg of aclidinium bromide by healthy subjects or COPD patients, the urinary excretion of unchanged aclidinium was very low at about 0.1% of the administered dose, indicating that renal clearance plays a minor role in the total aclidinium clearance from plasma.
Aclidinium bromide demonstrated kinetic linearity and a time-independent pharmacokinetic behaviour in the therapeutic range.
Elderly patients: The pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD appear to be similar in patients aged 40-59 years and in patients aged ≥70 years. Therefore, no dose adjustment is required for elderly COPD patients.
Hepatically-impaired patients: No studies have been performed on hepatically-impaired patients. As aclidinium bromide is metabolised mainly by chemical and enzymatic cleavage in the plasma, hepatic dysfunction is very unlikely to alter its systemic exposure. No dose adjustment is required for hepatically-impaired COPD patients.
Renally-impaired patients: No significant pharmacokinetic differences were observed between subjects with normal renal function and subjects with renal impairment. Therefore, no dose adjustment and no additional monitoring are required for renally-impaired COPD patients.
Race: Following repeated inhalations, the systemic exposure of aclidinium bromide has been observed to be similar in Japanese and Caucasian patients.
Because aclidinium bromide acts locally in the lungs and is quickly broken down in plasma there is no direct relationship between pharmacokinetics and pharmacodynamics.
Toxicology: Preclinical safety data:
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential and toxicity to reproduction and development.
Effects in nonclinical studies with respect to cardiovascular parameters (increased heart rates in dogs), reproductive toxicity (fetotoxic effects), and fertility (slight decreases in conception rate, number of corpora lutea, and pre- and post-implantation losses) were observed only at exposures considered sufficiently in excess of the maximum human exposure indication to be of little relevance to clinical use.
The low toxicity observed in nonclinical toxicity studies is in part due to rapid metabolism of aclidinium bromide in plasma and the lack of significant pharmacological activity of the major metabolites. The safety margins for human systemic exposure with 400 µg twice daily over the no observed adverse effect levels in these studies ranged from 7- to 73-fold.