Abstract
The inhaled, long-acting muscarinic antagonist, aclidinium bromide, was indicated in July 2012 in Europe and the USA for the maintenance of bronchodilator treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. Although initially investigated as a once-daily agent, a lower than expected improvement in trough forced expiratory volume over 1 s prompted re-evaluation as a twice-daily (b.i.d.) regimen. The dose approved for use in Europe, 400 μg b.i.d., achieved statistically significant improvements in lung function, reductions in breathlessness, and improved health-related quality of life (HRQoL) for up to 24 weeks of treatment in the pivotal phase 3 trials (AClidinium in Chronic Obstructive Respiratory Disease I [ACCORD COPD I] [12 weeks] and Aclidinium To Treat Airway obstruction In COPD patieNts [ATTAIN] [24 weeks]). These improvements were sustained during maintenance therapy of up to 52 weeks. Pooled data from the ATTAIN and ACCORD studies (both included a placebo arm) showed that exacerbation frequency was significantly reduced, although neither study was prospectively designed to evaluate this endpoint. Pharmacological and preclinical studies demonstrated the low systemic bioavailability of aclidinium and the low propensity to induce cardiac arrhythmias. The good tolerability of aclidinium was confirmed in the phase 3 program up to 52 weeks of treatment. The adverse event (AE) profile of the approved dose, 400 μg b.i.d., was similar to that of placebo, with a low incidence of anticholinergic and cardiac AEs. Aclidinium is delivered via the Genuair® multidose dry powder inhaler (Almirall Sofotec GmBH, Bad Homburg, Germany). The device is simple to use with multiple feedback mechanisms ensuring consistent dose delivery. In summary, aclidinium 400 μg b.i.d. is effective for the treatment of patients with COPD, offering improvements in lung function, breathlessness, and HRQoL, with a good safety profile and a low incidence of anticholinergic and cardiac AEs.
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Gavaldà A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009;331:740–51.
Prat M, Fernández D, Buil MA, et al. Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)acetyl] oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2] octane bromide (aclidinium bromide). J Med Chem. 2009;52:5076–92.
Global Initiative for Chronic Obstructive Pulmonary Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Revised 2011. Available at: http://www.goldcopd.org/guidelinesgold-summary-2011.html. Accessed Dec 17 2012.
Food and Drug Administration. FDA approves Tudorza Pressair to treat chronic obstructive pulmonary disease. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm313052.htm. Accessed Mar 1 2013.
European Medicines Agency. Eklira Genuair. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002211/smops/Positive/human_smop_000374.jsp&mid=WC0b01ac058001d127. Accessed Mar 1 2013.
Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res. 2011;12:55.
Barnes PJ. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med. 2004;117:24S–32S.
Gavaldà A, Vinyals M, Aubets J, Gras J. Effect of formoterol alone and in combination with aclidinium on electrocardiograms in dogs. Eur Respir J. 2012;40:376s. P2116. Available at: http://www.erscongress2012.org/. Accessed Mar 1 2013.
Albertí J, Martinet A, Sentellas S, Salvà M. Identification of the human enzymes responsible for the enzymatic hydrolysis of aclidinium bromide. Drug Metab Dispos. 2010;38:1202–10.
Ortiz S, Flach S, Caracta C, Garcia Gil E, Jansat JM. Safety and tolerability of aclidinium administered intravenously and absolute bioavailability of inhaled aclidinium in healthy male participants. J Clin Pharmacol. 2012;52:819–27.
Sentellas S, Ramos I, Albertí J, et al. Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: in vitro plasma inactivation and pharmacological activity of its main metabolites. Eur J Pharm Sci. 2010;39:283–90.
Lasseter KC, Aubets J, Chuecos F, Garcia Gil E. Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects. J Clin Pharmacol. 2011;51:923–32.
Schmid K, Pascual S, Garcia Gil E, Ortiz S, Jansat JM. Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: a phase I, open-label, single-dose clinical trial. Clin Ther. 2010;32:1798–812.
de la Motte L, Beier J, Schmid K, Pascual S, Jansat JM, Garcia Gil E. Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease. Int J Clin Pharmacol Ther. 2012;50:403–12.
Singh D, Magnussen H, Kirsten A, et al. A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. Pulm Pharmacol Ther. 2012;25:248–53.
Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest. 2012;141:745–52.
Kerwin EM, D’Urzo AD, Gelb AF, Lakkis H, Garcia Gil E, Caracta CF. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD. 2012;9:90–101.
Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40;830-6.
Forest Research Institute. Aclidinium bromide in chronic obstructive pulmonary disease. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM292624.pdf. Accessed Mar 4 2013.
Tashkin D, Gelb A, Make B, Zhong X, Garcia Gil E, Caracta C. Long-term efficacy of twice-daily aclidinium bromide in COPD patients: a one-year study. Eur Respir J. 2012;40:528s. P2893.
D’Urzo AD, Kerwin EM, Donohue JF, et al. Longterm extension study of ACCORD COPD I: effects of two doses of twice-daily aclidinium bromide in COPD patients. Am J Respir Crit Care Med. 2012;185:A2913.
Kerwin EM, Jones P, D’Urzo A, Rekeda L, Garcia Gil E, Caracta C. Twice-daily aclidinium bromide in COPD patients: a pooled analysis of lung function in the ACCORD COPD I and ATTAIN trial. Eur Respir J. 2012;40:528s. P2892.
Beier J, Kirsten AM, Mroz R, et al. Efficacy of aclidinium bromide compared with tiotropium and placebo in patients with moderate to severe COPD: a Phase IIIB study. Thorax. 2012;67:A147.
Agusti A, Jones PW, Bateman ED, et al. Improvement in symptoms and rescue medication use with aclidinium bromide in patients with chronic obstructive pulmonary disease: Results from ATTAIN. Eur Respir J. 2011;38:149. P874.
Jones PW. St George’s Respiratory Questionnaire: MCID. COPD. 2005;2:75–9.
Mahler DA. Witek TJ, Jr. The MCID of the transition dyspnea index is a total score of one unit. COPD. 2005;2:99–103.
Jones P, Singh D, Agusti A, et al. Aclidinium bromide in patients with chronic obstructive pulmonary disease (COPD): reduction in exacerbations as defined by health-care utilization and the EXACT diary card. Chest. 2011;140:529A.
Jones P, Singh D, Agusti A, et al. Aclidinium bromide reduces COPD exacerbations as defined by healthcare utilisation and EXACT: results from ATTAIN. Eur Respir J. 2012;40:9s. 195.
Jones P, Singh D, Kerwin E, Lamarca R, Caracta C, Garcia Gil E. Reduced COPD exacerbations associated with aclidinium bromide versus placebo: a pooled analysis of phase III data. Thorax. 2012;67:A146.
Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S. Standardizing measurement of chronic obstructive pulmonary disease exacerbations. Reliability and validity of a patient-reported diary. Am J Respir Crit Care Med. 2011;183:323–9.
Maltais F, Celli B, Casaburi R, et al. Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. Respir Med. 2011;105:580–7.
Jansat JM, Lamarca R, Garcia Gil E, Ferrer P. Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled muscarinic, in healthy subjects. Int J Clin Pharmacol Ther. 2009;47:460–8.
Jansat JM, Lamarca R, de Miquel G, Schrödler A, Miletzki B, Gurniak M. Safety and pharmacokinetics of multiple doses of aclidinium bromide, a novel long-acting muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, in healthy participants. J Clin Pharmacol. 2009;49:1239–46.
Lasseter K, Dilzer S, Jansat JM, Garcia Gil E, Caracta CF, Ortiz S. Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers. Pulm Pharmacol Ther. 2012;25:193–9.
Ortiz S, Flach S, Ho J, et al. Mass balance and metabolism of aclidinium bromide following intravenous administration of [14C]-aclidinium bromide in healthy subjects. Biopharm Drug Dispos. 2012;33:39–45.
Gelb AF, Tashkin D, Make B, Zhong X, Garcia Gil E, Caracta C. Long-term safety of twice-daily aclidinium bromide in COPD patients: a one-year, double-blind study. Eur Respir J. 2012;40:376s. P2118.
Chrystyn H, Niederlaender C. The Genuair® inhaler: a novel, multidose dry powder inhaler. Int J Clin Pract. 2012:66:309–17.
Kurtz S, Block K, Folger S, Pieper T, Fyrnys B. Drug product stability of aclidinium bromide in Genuair®. Eur Respir J 2012;40:384s. P2156.
Van der Palen J, Ginko T, Kroker A, et al. Preference, satisfaction and critical errors with Genuairand HandiHalerin patients with COPD. Eur Respir J. 2012;40:389s. P2177.
Hass C, Engdahl K, Albert W, Setyawan J, Mateo N. Patient preferences and perceived ease of use in inhaler features: Genuair vs other inhalers. Chest. 2010;138;484A.
Fuhr R, Magnussen H, Singh D, de Miquel G, Caracta C, Garcia Gil E. Patient assessments of ease of use of Genuair® versus Aerolizer® and HandiHaler®. Eur Respir J. 2011;38:725s. P3979.
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Jones, P. Aclidinium Bromide Twice Daily for the Treatment of Chronic Obstructive Pulmonary Disease: A Review. Adv Therapy 30, 354–368 (2013). https://doi.org/10.1007/s12325-013-0019-2
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DOI: https://doi.org/10.1007/s12325-013-0019-2