Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß<sub>2</sub>-Agonist, Is Effective in COPD Patients.

Noord, JA van; Korducki, Lawrence; Hamilton, AL; Koker, Paul

doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a6183

Cited by 14 publications

(15 citation statements)

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“…In all studies, olodaterol showed a 24-h duration of action after once-a-day dosing concomitant with a good safety profile. The 24-h bronchodilator efficacy of once-daily dosing with olodaterol in patients with COPD was confirmed in a 4-week study, with all doses of olodaterol showing statistically significant increases in the primary endpoint, trough FEV 1 (forced expiratory volume in 1 second), compared with placebo after 28 days of treatment, again with an excellent safety profile (Van Noord et al, 2009). Furthermore, in the 4-week study no differences in the FEV 1 profile after the first dose (day 1) and after 4 weeks of treatment (day 29) were observed, implying the absence of clinical desensitization noted in some clinical studies after regular use of ␤ 2 -adrenoceptor agonists (Larj and Bleecker, 2002).…”

Section: Discussionmentioning

confidence: 83%

Pharmacological Characterization of Olodaterol, a Novel Inhaled β₂-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

Bouyssou

Casarosa

Naline

et al. 2010

J Pharmacol Exp Ther

110

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The preclinical pharmacological profile of 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one monohydrochloride (olodaterol, previously known as BI 1744 CL), a novel, enantiomeric pure, inhaled human ␤ 2 -adrenoceptor (h␤ 2 -AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the h␤ 2 -AR (EC 50 ϭ 0.1 nM; intrinsic activity ϭ 88% compared with isoprenaline) and a significant selectivity profile (219-and 1622-fold against the h␤ 1 -and h␤ 3 -ARs, respectively). Likewise, olodaterol was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, antagonistic effects of single doses of olodaterol and formoterol were measured against acetylcholine challenges in anesthetized guinea pigs and dogs for up to 24 h by using the Respimat Soft Mist inhaler. Heart rate and metabolic parameters (serum potassium, lactate, and glucose) were monitored to evaluate systemic pharmacodynamic effects in the dog model. In both models, olodaterol provided bronchoprotection over 24 h. Formoterol applied at an equally effective dose did not retain efficacy over 24 h. In both models olodaterol showed a rapid onset of action comparable with formoterol. Taken together, the preclinical behavior of olodaterol suggests that this novel ␤ 2 -AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile.Asthma and chronic obstructive pulmonary disease (COPD) are conditions characterized by airway obstruction, which is variable and reversible in asthma but is progressive in COPD (Guerra, 2009). Both diseases are very common, and their incidence is increasing globally, placing a growing burden on patients and health services in industrialized and developing countries (Pauwels and Rabe, 2004;Braman, 2006). ␤ 2 -Adrenoceptor (␤ 2 -AR) agonists are among the most potent and rapidly acting bronchodilators currently available for clinical use. In asthma, rapid-acting inhaled ␤ 2 -AR agonists are the therapy of choice as a reliever therapy for episodes of dyspnea and the pretreatment of exercise-induced bronchoconstriction (Bateman et al., 2008). In asthma patients with persistent symptoms long-acting ␤-agonists (LABAs), such as salmeterol and formoterol, are administered as an add-on controller therapy when the first-line treatment of medium dose-inhaled corticosteroids alone fails to achieve control of asthma (Bateman et al., 2008). Recently, formoterol has gained some recognition as an as needed controller therapy because of its fast onset of action. In addition, inhaled ␤ 2 -AR agonists provide major therapeutic benefits in the treatment of COPD, such as reduction in symptoms and exacerbations, increases in exercise capacity, and improvements of health-related quality of life (Gold, 2009).␤ 2 -AR agonists exert a bronchodilatory effect through activation of ...

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Section: Discussionmentioning

confidence: 83%

Pharmacological Characterization of Olodaterol, a Novel Inhaled β₂-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

Bouyssou

Casarosa

Naline

et al. 2010

J Pharmacol Exp Ther

110

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“…Olodaterol was identified as part of a program aimed at the discovery of selective ␤ 2 -AR agonists with the potential for oncedaily administration, as shown in clinical studies in both asthma and COPD patients (O'Byrne et al, 2009;Van Noord et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol

Casarosa¹,

Kollak²,

Kiechle³

et al. 2011

J Pharmacol Exp Ther

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␤ 2 -Adrenoceptor (␤ 2 -AR) agonists are powerful bronchodilators and play a pivotal role in the management of pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease. Although these agents first were used many years ago, progress in drug development has resulted in better tolerated, long-acting ␤ 2 -AR agonists (LABAs), such as formoterol and salmeterol. Although LABAs have been on the market for several years, relatively little is known on the rationale(s) behind their long duration of action. In this study, we focused on olodaterol (previously known as BI1744CL), a novel inhaled LABA, which provides a bronchodilating effect lasting 24 h and is currently in Phase III clinical trials. To understand the rationale behind its long duration of action, different aspects of olodaterol were analyzed (i.e., its lipophilicity and propensity to accumulate in the lipid bilayer as well as its tight binding to the ␤ 2 -AR). In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. Instead, kinetic as well as equilibrium binding studies indicated the presence of a stable [ 3 H]olodaterol/␤ 2 -AR complex with a dissociation half-life of 17.8 h due to ternary complex formation. The tight binding of olodaterol to the human ␤ 2 -AR and stabilization of the ternary complex were confirmed in functional experiments monitoring adenylyl cyclase activity after extensive washout. Taken together, binding, kinetic, and functional data support the existence of a stable complex with the ␤ 2 -AR that, with a dissociation half-life Ͼ17 h, might indeed be a rationale for the 24-h duration of action of olodaterol.

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“…The efficacy of BI-1744-CL has been examined in a doubleblind placebo-controlled five-way crossover phase II trial in 36 patients with stable COPD [41,44]. After a 2-week run-in, subjects were randomised to either placebo or 2, 5, 10 or 20 mg BI-1744-CL.…”

Section: Copdmentioning

confidence: 99%

Emerging inhaled bronchodilators: an update

Cazzola¹,

Matera²

2009

Eur Respir J

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Bronchodilators remain central to the symptomatic management of chronic obstructive pulmonary disease and asthma, and, for this reason and also because the patent protection of many bronchodilators has expired, several companies have reinitiated research into the field.The only limits set for the development of a long-lasting bronchodilator with a new product profile are medical needs and marketing opportunities. The incorporation of once-daily dose administration is an important strategy for improving adherence and is a regimen preferred by most patients.A variety of b 2 -agonists and antimuscarinic agents with longer half-lives and inhalers containing a combination of several classes of long-acting bronchodilator are currently under development.The present article reviews all of the most important compounds under development, describing what has been done and discussing their genuine advantage.

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Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß₂-Agonist, Is Effective in COPD Patients.

Cited by 14 publications

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Pharmacological Characterization of Olodaterol, a Novel Inhaled β₂-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

Pharmacological Characterization of Olodaterol, a Novel Inhaled β₂-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol

Emerging inhaled bronchodilators: an update

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Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß2-Agonist, Is Effective in COPD Patients.

Cited by 14 publications

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Pharmacological Characterization of Olodaterol, a Novel Inhaled β2-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

Pharmacological Characterization of Olodaterol, a Novel Inhaled β2-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol

Emerging inhaled bronchodilators: an update

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Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß₂-Agonist, Is Effective in COPD Patients.

Pharmacological Characterization of Olodaterol, a Novel Inhaled β₂-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

Pharmacological Characterization of Olodaterol, a Novel Inhaled β₂-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models