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Imidafenacin, an Orally Active Muscarinic Receptor Antagonist, Improves Pulmonary Function in Patients with Chronic Obstructive

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Imidafenacin, an Orally Active Muscarinic Receptor Antagonist, Improves Pulmonary Function in Patients with Chronic Obstructive International Journal of Chronic Obstructive Pulmonary Disease Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Imidafenacin, An Orally Active Muscarinic Receptor Antagonist, Improves Pulmonary Function In Patients With Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled 3×3 Crossover Phase II Trial This article was published in the following Dove Press journal: International Journal of Chronic Obstructive Pulmonary Disease Kentaro Machida, 1,* Background: Although long-acting muscarinic receptor antagonists are central to the To m o t a k a K aw ay a m a , 2,* management of chronic obstructive pulmonary disease (COPD), inhaled medicines may 3, Masaharu Kinoshita, * have technical difficulty in some patients and adherence barriers. 4 5 Masakazu Ichinose, To h r u T s u d a , Methods: A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase 6 7 Shohei Takata, Hiroshi Koto, II trial was performed to evaluate the efficacy and safety of oral administration of the Makoto Yoshida,8 Yoshinori Ashihara,9 antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD Masaru Kawashima,10 Hideaki Suna,10 patients with % forced expiratory volume in 1 s (FEV ) ≥30% and <80% predicted were Hiromasa Inoue 1 1 randomized to single oral dose of imidafenacin 0.1 mg, imidafenacin 0.2 mg, or placebo. 1 Department of Pulmonary Medicine, Graduate Results: Maximum change in FEV with both doses of imidafenacin significantly improved from School of Medical and Dental Sciences, Kagoshima 1 University, Kagoshima 890-8520, Japan; 2Division baseline to 24 hrs after administration when compared with a placebo. Area under the curve in of Respirology, Neurology, and Rheumatology, FEV1 during 24 hrs after administration with 0.2 mg, but not 0.1 mg dose, was significantly Department of Medicine, Kurume University fi School of Medicine, Kurume 830-0011, Japan; improved when compared with a placebo, and the improvement was signi cantly based on dose- 3Nagata Hospital, Yanagawa 832-0059, Japan; dependent manners. Plasma imidafenacin level was positively correlated with change in FEV1.All 4Department of Respiratory Medicine, Tohoku University, Graduate School of Medicine, Sendai subjects with both doses of imidafenacin completed without moderate nor severe adverse events. 980-8574, Japan; 5Kirigaoka Tsuda Hospital, Conclusion: A single oral dose of imidafenacin 0.1 mg or imidafenacin 0.2 mg may 6 Kitakyushu 802-0052 Japan; Division of contribute to the improvement of pulmonary function with excellent safety and tolerability Respiratory Medicine, National Hospital Organization Fukuoka-Higashi Medical Center, in patients with COPD. 7 Koga 811-3195, Japan; Division of Respiratory Trial registration: JapicCTI-121760 (Japan Pharmaceutical Information Center – Clinical Medicine, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka Trials Information [JapicCTI]; http://www.clinicaltrials.jp/user/cteSearch_e.jsp). 8 815-8588, Japan; Division of Respiratory Medicine, Keywords: anti-cholinergic, bronchodilator, imidafenacin, lung function, COPD National Hospital Organization Fukuoka Hospital, Fukuoka 811-1394, Japan; 9Division of Respiratory Medicine, Oita Nakamura Hospital, Oita 870-0022, Japan; 10ONO Pharmaceutical Co. Ltd., Osaka 541- 8564, Japan Introduction *These authors contributed equally to this work Long-acting bronchodilators play a central role in the management for patients with chronic obstructive pulmonary disease (COPD), which is characterized by persistent 1 airflow limitation. Long-acting muscarinic 3 (M3) receptor antagonists (LAMAs) and β2-agonists (LABA) are well known to improve lung function, quality of life (QOL), Correspondence: Hiromasa Inoue Department of Pulmonary Medicine, exercise tolerance, and attenuate frequency and severity of exacerbations and mortality in Graduate School of Medical and Dental stable patients with COPD.2–7 To maximize the bronchodilation via direct effects and Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan minimalize the systemic effects, every medicine of LAMAs is inhalant for management Tel +81 99 275 6481 of chronic respiratory diseases.8–11 However, some patients, especially elderly, with Fax +81 99 275 6482 12,13 Email [email protected] COPD have difficulty in mastering inhalation techniques. submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2175–2184 2175 DovePress © 2019 Machida 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 http://doi.org/10.2147/COPD.S223002 work you 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). Machida et al Dovepress Oral bronchodilators may potentially be more conveni- the Ethics Committee of each institution. After providing ent, particularly for less compliant patients and those who written informed consents, screening, and a 4-week run-in have difficulty using inhaled medicines. Imidafenacin, 4-(2- period, eligible patients were randomized to three separated methyl-1-H-imidazol-1-yl)-2,2-diphenyl butanamide, is one 1-day treatment periods (Figure 1). Laboratory tests, vital of the LAMAs with high affinity for the M3 and M1 mus- signs, and a 12-lead electrocardiogram (ECG) were assessed carinic receptor subtypes and low affinity for the M2 at the screening visit. The treatments comprised a single dose 14 subtype. The M3 subtype is expressed on airway smooth of oral imidafenacin 0.1 mg, imidafenacin 0.2 mg, or pla- muscle and mediates bronchoconstriction. In contrast, pre- cebo. All doses were administered in the morning between junctional M2 receptors are expressed in nerves innervating 08:00 and 10:00. Each treatment period was separated by a the heart and lungs and inhibit the release of acetylcholine, 7–28-day washout period. and inhibition of the M2 subtype potentially increases the risk of bronchoconstriction and tachycardia. Therefore, we Subjects hypothesized that imidafenacin may have fewer side effects, Japanese male or female patients aged ≥40 years with stable ≤ allowing higher exposure and a favorable therapeutic margin. COPD stages II and III (an FEV1/FVC ratio <0.70 and 30% ˂ Doses of 0.1 mg–0.2 mg of oral imidafenacin already have %FEV1 80% predicted at post-bronchodilator: 2 puffs of established safety and tolerability in patients with overactive salbutamol) according to the Global Initiative for Chronic 1 bladder worldwide including Japan.15,16 Obstructive Lung Disease (GOLD) reports modified in 2010 Preclinical studies demonstrated that oral administra- and who had a smoking history of ≥10 pack-years were tion of imidafenacin inhibited methacholine-induced bron- enrolled in the trial. Patients with a history of asthma, lung chial constriction in a dose-dependent manner in guinea cancer, bronchiectasis, diffuse panbronchiolitis, sinobron- pigs (Figure S1). To verify a hypothesis based on the chial syndrome, interstitial pneumonia, tuberculosis, and preclinical results that imidafenacin can improve pulmon- active malignancies were excluded. Patients with surgery of ary function, we conducted a multicenter, randomized, lungs, pregnant, nursing, and contraindications for imidafe- double-blind, placebo-controlled crossover Phase II trial nacin were also excluded. Patients with long-term oxygen ≥ with a 3×3 design, wherein the efficacy and safety of oral therapy ( 15 hrs/day) were also excluded. imidafenacin were examined in patients with COPD. Medication Restrictions A list of contraindicating medicines and periods of non- Methods recognition prior to pulmonary function tests at each visit Study Design are shown below; inhaled short-acting β2-agonists and mus- To assess the efficacy and tolerability of two single doses carinic receptor antagonists for 8 hrs and 12 hrs, respec- of oral imidafenacin (0.1 mg and 0.2 mg) in patients with tively, twice-daily and once-daily inhaled LABAs for 24 COPD, a multicenter, randomized, placebo-controlled, and 48 hrs, respectively, oral or transdermal β2-agonists for double-blind, three-treatment tertiary stage, crossover 24 hrs, LAMAs, injected or oral muscarinic receptor study was intended. The primary endpoint was the max- antagonists, and cholinergic agonists for 7 days, and imum change in forced expiratory volume in 1 s (FEV1) twice-daily and once-daily theophylline for 24 and 48 hrs, from baseline at various times during 24 hrs after admin- respectively. Contraindication medicines were prohibited istration of oral imidafenacin 0.1 mg or 0.2 mg. The until the last administration of the study medications. secondary endpoint was the area under the curve (AUC) Systemic corticosteroids, anti-allergic or histaminic agents, of FEV1 from baseline to 24 hrs after administration and injective methylxanthines were not accepted for COPD- (AUC24h). The forced vital capacity (FVC), peak expira- related exacerbations through the trial. tory flow (PEF), maximal mid-expiratory
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