Journal name: International Journal of COPD Article Designation: Review Year: 2016 Volume: 11 International Journal of COPD Dovepress Running head verso: Incorvaia et al Running head recto: Striving for optimal bronchodilation open access to scientific and medical research DOI: http://dx.doi.org/10.2147/COPD.S96070 Open Access Full Text Article REVIEW Striving for optimal bronchodilation: focus on olodaterol 1 Cristoforo Incorvaia Abstract: β2-agonists were introduced in the 1940s as bronchodilators to be used in obstructive 2 Marcello Montagni respiratory diseases. Long-acting β2-agonists have been a mainstay of bronchodilating treat- Elena Makri1 ment for decades. Recently, agents extending their effect to 24 hours and thus allowing the once-daily administration were introduced, defined as very-long-acting -agonists. Olodaterol Gian Galeazzo Riario- β2 1 is a new very-long-acting β -agonist that has been shown, in controlled trials, to improve lung Sforza 2 Erminia Ridolo2 function as well as clinical outcomes and quality of life. Most of these trials included patients with moderate, severe, or very severe chronic obstructive pulmonary disease (COPD). Olo- 1 Allergy/Pulmonary Rehabilitation, daterol has a rapid onset of action (comparable to formoterol) and provides bronchodilation Istituti Clinici di Perfezionamento Hospital, Milan, Italy; 2Department of over 24 hours. In controlled trials, olodaterol was shown to be as effective as formoterol twice Clinical and Experimental Medicine, daily, but significantly superior in terms of quality of life in patients with COPD. The safety University of Parma, Parma, Italy profile of olodaterol was very good, with a rate of adverse events, including the cardiac events For personal use only. that are particularly important for β2-agonists, comparable to placebo. Also, the efficiency of the Respimat® device concurs to the effectiveness of treatment. Keywords: bronchodilators, β2-agonists, very long acting, olodaterol, efficacy, safety, COPD Introduction The first drugs aimed at obtaining bronchodilation in patients with asthma were aminophyllines in the 1940s.1 In the same years, drugs acting on the β-adrenoreceptor were developed, starting with isoproterenol and including in the following years salbu- tamol, orciprenaline, and terbutalin.2 Such drugs could be administered by injective, oral, and respiratory routes, but it was soon apparent that the safety and tolerability were significantly better with the respiratory route, especially regarding adverse effects on heart rate and blood pressure (that are due to stimulation of cardiac and vascular β-adrenoreceptors).3,4 The main limitation of these agents was the short duration of bronchodilation, defining them as short-acting β2-agonists (SABAs) and requiring several inhalations each day with obvious problems of adherence. The next step was International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 54.70.40.11 on 18-Dec-2018 the development in the 1980s of β2-agonists with prolonged activity of bronchodilation, allowing two inhalations per day, such as salmeterol5 and formoterol.6 These drugs were defined as long-actingβ 2-agonists (LABAs) and became a common treatment of asthma7 and chronic obstructive pulmonary disease (COPD).8,9 From the 2000s, a new generation of β2-agonists is being developed, with a very prolonged bronchodilation that allows for once-daily dosing and makes them suitable for maintenance treatment of Correspondence: Cristoforo Incorvaia asthma and COPD. The first agent of this class demonstrating efficacy and safety was Allergy/Pulmonary Rehabilitation, ICP Hospital, Via Bignami 1, 20126 Milan, Italy indacaterol.10 Because of its prolonged duration of action, a denomination of “ultra- Tel +39 02 5799 3289 LABA” was proposed,11 but defining these drugs as “very-long-acting -agonists Fax +39 02 5799 3579 β2 Email [email protected] (VLABAs)” seems to fit better with the usual nomenclature.12 Other VLABAs were submit your manuscript | www.dovepress.com International Journal of COPD 2016:11 439–444 439 Dovepress © 2016 Incorvaia et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/COPD.S96070 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Incorvaia et al Dovepress recently introduced, such as vilanterol13 and olodaterol.14 with fast flow rate, a DPI with slow flow rate, and an MDI.24 As yet, vilanterol is available only in combination with the The first drug administered by Respimat® Soft Mist™ inhaler inhaled corticosteroid (ICS) fluticasone furoate15 and with the was tiotropium, which allowed a dose reduction from 18 μg long-acting muscarinic antagonist (LAMA) umeclidinium,16 with the DPI HandiHaler to 5 μg with the new device. In a while olodaterol is available as single agent or in combina- recent review, in patients with COPD, tiotropium Respimat® tion with the LAMA tiotropium,17 both administered by the improved lung function, COPD exacerbations, health-related device Respimat® Soft Mist™ inhaler (Boehringer Ingelheim, quality of life, and dyspnea and showed an increase in Ingelheim, Germany).18 efficacy and safety comparable to tiotropium HandiHaler® Here, we review the literature on olodaterol to focus its (Boehringer Ingelheim, Ingelheim, Germany), despite the possible role in the treatment of COPD. dose reduction to less than one-third.25 Pharmacological profile of Controlled trials on efficacy and olodaterol safety of olodaterol Olodaterol exerts its pharmacological effects by binding and The efficacy of olodaterol was shown by several large activating β2-adrenoceptors on human airway smooth muscle Phase III trials in terms of improvement in lung function as cells after topical administration by inhalation. Moreover, well as clinical outcomes and quality of life. Most of these olodaterol is very highly selective for β2 receptors as shown trials included patients with moderate, severe, or very severe by in vitro studies that have detected that olodaterol has 241- COPD, defined as a postbronchodilator forced expiratory vol- fold greater agonist activity at β2-adrenoceptors compared ume in 1 second (FEV1) ,80% of the predicted value and a 19 to β1-adrenoceptors. Activation of these receptors in the postbronchodilator FEV1/forced vital capacity ,70% (Global airways results in a stimulation of intracellular enzyme adenyl initiative for chronic Obstructive Lung Disease [GOLD] cyclase that mediates the synthesis of cyclic-3′,5′ adenosine 2–4). Also, the potential benefits of combined treatment monophosphate (cAMP). Elevated levels of cAMP induce with olodaterol and tiotropium (fixed dose administered via For personal use only. bronchodilation by relaxation of airway smooth muscle Respimat® or administered separately with different device) cells.20 Olodaterol also dose-dependently reversed the con- were investigated. In a first single-center, double-blind, striction induced by different stimuli, such as histamine and placebo-controlled, five-way crossover study, dose- and acetylcholine.19 In vivo, olodaterol showed a rapid onset time-response, safety, and tolerability of once-daily dosing of action (comparable to those obtained with formoterol) of 2, 5, 10, and 20 μg olodaterol was assessed in patients with and provided bronchoprotection over 24 hours. In addition, COPD.26 All doses of olodaterol provided significantly greater anti-inflammatory effects of olodaterol were demonstrated in bronchodilation compared to placebo in 24-hour postdosing 21 pulmonary fibroblasts in vitro, but the clinical significance FEV1 (trough FEV1) (P,0.001) with a clear dose–response of such an observation needs to be investigated in patients relationship. Moreover, olodaterol was superior to placebo with obstructive respiratory disease. (P,0.001) in peak and average FEV1 both during the daytime (0–12 hours) and nighttime (12–24 hours). Two replicate, ran- Characteristics of the inhalation domized, double-blind, placebo-controlled, parallel-group, device Phase III trials, including 624 and 642 patients, respectively, The Respimat® Soft Mist™ inhaler is a propellant-free inhaler were then performed in order to investigate the long-term International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 54.70.40.11 on 18-Dec-2018 based on a mechanical device generating a solution contain- safety and efficacy of olodaterol delivered via the Respimat® ing the drug with a smooth and slow aerosol cloud well-fitting inhaler in patients with moderate to very severe COPD.27 In with human inhalation.22 Most aerosol particle masses have these trials, patients were randomized to receive olodaterol a diameter of 1–5 mm, with a high proportion belonging 5 or 10 μg or placebo once daily for 48 weeks. FEV1 area to the fine particle fraction, ie, with a diameter ,5.8 mm, under the curve from 0 to 3 hours (AUC0–3) response (change and this makes the penetration