|Year : 2021 | Volume
| Issue : 1 | Page : 16-21
Feasibility of testing bronchodilator responsiveness with glycopyrronium in obstructive airway diseases: the initial appraisal of the pilot experience
Parthasarathi Bhattacharyya, Dipanjan Saha, Sayoni Sengupta, Debkanya De
Department Pulmonary Medicine, Institute of Pulmocare and Research, Kolkata, India
|Date of Submission||02-Jun-2020|
|Date of Decision||20-Jun-2020|
|Date of Acceptance||07-Jan-2021|
|Date of Web Publication||15-Feb-2021|
Dr. Parthasarathi Bhattacharyya
Parthasarathi Bhattacharyya, Institute of Pulmocare and Research, DG-8, Action area-1, New Town, Kolkata 700156
Source of Support: None, Conflict of Interest: None
Background: The short onset of action of glycopyrronium bromide, makes it a suitable antimuscarinic agent to test bronchodilator-responsiveness in airway diseases. The objective of the study was to explore the feasibility of the testing so. Methods: Subjects with features of airflow obstruction (FEV1/FVC < 0.07) were given to inhale a 50-μg single dose of dry powder of glycopyrronium bromide immediately following standard salbutamol-induced bronchodilator reversibility. A repeat spirometry was done after 30 minutes and the changes noted. The impact of both the drugs on spirometric variables suggesting airflow obstruction (FEV1. FEV1/FVC, and FEF25-75) were assessed statistically. A salbutamol-reversibility of ≥12% and >200ml was noted to differentiate asthmatics from chronic obstructive pulmonary disease (COPD) patients. Result: In a total of 35 subjects (asthma-10, COPD-25) with moderate baseline airflow obstruction [FEV1/FVC: 0.57 ± 0.12 and FEV1 (%predicted) as 46.17 ± 15.21], there was global improvement across the spirometric variables to serial inhalation of salbutamol and glycopyrronium. The post salbutamol changes in FEV1 (absolute value) were significant (P = 0.0001) overall and also for both asthma and COPD. Following inhalation of glycopyrronium, the changes were again significant for overall (P = 0.0001), asthma (P = 0.0065), and COPD (P = 0.0001). The parallel change in FEF25-75 was, however, showing better reversibility in asthma (P = 0.0008) with salbutamol compared to COPD (P = 0.1846) and the reverse to glycopyrronium inhalation that results in better reversibility in COPD (P = 0.0085) compared to asthma (P = 0.0949). Conclusion: Testing the reversibility with glycopyrronium appears feasible and safe in obstructive airway disease. It induced add-on reversibility once used after standard salbutamol reversibility. The observation demands further evaluations.
Keywords: Asthma, bronchodilator reversibility, COPD, glycopyrronium bromide, obstructive airway disease, salbutamol
|How to cite this article:|
Bhattacharyya P, Saha D, Sengupta S, De D. Feasibility of testing bronchodilator responsiveness with glycopyrronium in obstructive airway diseases: the initial appraisal of the pilot experience. J Assoc Chest Physicians 2021;9:16-21
|How to cite this URL:|
Bhattacharyya P, Saha D, Sengupta S, De D. Feasibility of testing bronchodilator responsiveness with glycopyrronium in obstructive airway diseases: the initial appraisal of the pilot experience. J Assoc Chest Physicians [serial online] 2021 [cited 2021 Feb 28];9:16-21. Available from: https://www.jacpjournal.org/text.asp?2021/9/1/16/309474
| Introduction|| |
Airflow limitation and variable reversibility to bronchodilator signify an obstructive airway disease. The diagnosis of airflow limitation is determined by spirometry that accounts for several expiratory parameters such as FVC (forced vital capacity) and FEV1 (forced expiratory volume in the first one second). An FEV1/FVC ratio less than 0.70 signifies airflow obstruction and identifies chronic obstructive pulmonary disease (COPD). Such diagnosis is followed by a bronchodilator reversibility test using inhaled β2 agonist and salbutamol. Asthma tends to show higher reversibility. Determination of reversibility or responsiveness to β2 agonist helps to identify subjects who are likely to improve especially from this class of drugs.
The antimuscarinic agents (AMA) are another class of bronchodilators; they are often added to the therapy with β2 agonists with their add-on beneficial effects been recognized., Although these classes of drugs are available from a long time, there has been no way to predict the responsiveness of a patient to this class of drugs as they are mostly slow acting, and optimal bronchodilatation takes a longer duration making the reversibility test not feasible.
Of late, a new member of the group (AMA) has been introduced named glycopyrronium. It acts fast, within 5 minutes, and provides a good bronchodilator effect in 30 minutes., Because a patient can be kept waiting for a test for 30 minutes, this pharmacokinetic property makes us attempt the agent to be used to test its responsiveness in patients with obstructive airway diseases. The study deals with the initial experience.
| Methods|| |
The research was taken up with ethical clearance from the independent Ethics Committee of the Institute of Pulmocare and Research (registration number- ECR/159/Inst/WB/2013/RR-20). The patients were recruited on signing proper informed consent forms.
All the patients recruited had historically suggestive symptoms of OLD (cough, shortness of breath, wheeze) with or without a history of smoking or exposure to noxious gases. They were all symptomatic on some or other treatment but none of them was an active smoker. They were not on any antimuscarinic agent alone or in combination with β2 agonist or any systemic steroid and there was no history of any obvious exacerbation in the preceding six weeks. Very sick patients and patients unwilling to participate were excluded. Patients with closed-angle glaucoma, suspected or diagnosed (symptomatic or on medication) having benign prostatic hypertrophy, and tachycardia (resting pulse rate >100 ml) were also excluded along with those having a previous history of intolerance to glycopyrronium or atropine. Any patient with clinico-radiological suspicion of bronchiectasis or any other concomitant pleuropulmonary disease and those who did not show the feature of airflow obstruction (FEV/FVC < 0.7) following spirometry were not included. The spirometry with routine bronchodilator reversibility were done observing the ATS guideline.  Consecutive patients having features of airflow obstruction (post-bronchodilator FEV/FVC < 0.7) and qualifying the inclusion-exclusion criteria were selected for immediate add-on use of glycopyrronium after the routine bronchodilator test with salbutamol. The patients included were given 50 μg of glycopyrronium bromide dry powder (AIRZ rotacaps, Glenmark Pharmaceuticals Limited, Mumbai) with lupihaler (Lupin laboratories limited, Mumbai) to inhale immediately following this traditional bronchodilator reversibility test and their spirometry was repeated after 30 minutes. The results of the post glycopyrronium spirometry were recorded.
We observed the GOLF 2017 guideline for the diagnosis of COPD but for the diagnosis of asthma, we used the old Expert Panel-3 criteria of 200 ml and 12 % reversibility in face of episodic symptoms and no apparent alternate diagnosis. The statistical exercise was made with the common spirometry variables related to airflow limitations as FEV1/FVC, FEV1, and FEF25-75 (both in terms of their absolute values and the predicted percentages) using GraphPad Prism (version 7) software. Student t-test was applied for intergroup and intragroup assessments to see the impact of the two different bronchodilators given serially.
| Results|| |
We had a total of only 35 recruits; of them, 10 patients were asthmatic as per the expert panel report (EPR) criterion and 25 were suffering from COPD. The mean age was 56 ± 12.40, 63.44 ± 8.86, and 61.31 ± 10.38 years respectively for asthma and COPD and overall population with the baseline FEV1 of these three groups being 1.41 ± 0.46, 1.16 ± 0.43, and 1.28 ± 0.44 liters, respectively. The salbutamol responsiveness was maximum with asthma [300 ml (95% CI, 248–351) (P = 0.0001)] followed by overall [135 ml (95% CI, 92–178; P = 0.0001)] and thereafter COPD [70 ml (95% CI, 42–97; P = 0.0001)] [see [Table 1]. The glycopyrronium-induced reversibility was 95 ml (95% CI, 33–156 ml) for asthma (P = 0.0065), 72 ml (95% CI, 42–102 ml) for COPD (P = 0.0001), and 79 ml (95% CI, 53–105 ml) for the overall (P = 0.0001) patients [see [Table 1]. The improvement in FEV1/FVC was significant only in asthma to salbutamol (P = 0.002) [see [Table 1]. Although there was a global improvement in FEF25-75, it was significantly improved after salbutamol in asthma and the overall patients (P = 0.0008 and P = 0.0019) but the improvement after glycopyrronium was significant in COPD (P = 0.0085) and the overall groups (P = 0.001) [see [Table 1]. The trend lines of the changes are depicted in [Figure 1]. The procedure appeared acceptable to the volunteers on direct questioning and there was no adverse reaction of glycopyrronium in any of them.
|Table 1 Demographic details with lung function change in patients of airway diseases following salbutamol and then glycopyrronium induced bronchial responsiveness test|
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|Figure 1 The trend of change in different spirometric parameters following salbutamol and then glycopyrronium inhalation.|
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[Table 1] elaborates the changes in the parameters of obstruction as FEV1, FEV1/FVC, and FEF25-75 in the overall patients as well as COPD and asthma separately following serial reversibility test with salbutamol followed by glycopyrronium.
[Figure 1] shows the trend in change of the obstructive parameters in spirometry (FEV1, FEV1/FVC, and FEF25-75) in overall patients, patients with asthma, and COPD separately.
| Discussion|| |
We have tested the FEV1 reversibility in 35 patients of airflow obstruction (10 asthmatics and 25 COPD sufferers) with 50 μg, single-dose dry powder inhalation of glycopyrronium bromide immediately following standard bronchodilator reversibility test with salbutamol. There was a global improvement as a whole and also in each group (asthma and COPD) following both salbutamol and subsequent glycopyrronium inhalation. These changes were most impressive and mostly highly significant (P = 0.0001) for FEV1 [see [Table 1].
The observation, therefore, suggests that inhalation of glycopyrronium after standard bronchodilator reversibility test can make a significant add-on bronchodilatation that translates to 8.13% in asthma, followed by 7.27% in the “overall” group and 6.93% in COPD in terms of change in percentage predicted FEV1. However, as regards the reversibility of airflow obstruction in small airways, glycopyrronium inhalation appears to produce a more efficient bronchodilation in COPD as reflected in the changes in FEF25-75.
It is noteworthy that glycopyrronium inhalation in both COPD and asthma shows a wide range of bronchodilatation as evident from wide 95% confidence intervals [see [Table 1]. This suggests that there is probably a wide difference of cholinergic tone in different patients in each group and that a scope exists to select out subjects with higher responsiveness to an antimuscarinic agent. Thus, such efforts can help to identify AMA responders and individualize bronchodilator therapy or prescription of glycopyrronium in a particular patient.
The bronchodilator reversibility testing has been in use for a long time for patients with obstructive airway diseases. It helps to preemptively identify the treatment-responders with quantification of bronchodilator reversibility leading to a diagnosis of asthma earlier  Of late, guidelines consider the FEV1/FVC ratio as <0.7 being a marker of airflow obstruction and a diagnosis of COPD. However, the bronchodilator reversibility or responsiveness remained an integral and important part of the evaluation of diseases of airflow limitation. Traditionally this reversibility or responsiveness is tested by inhaled salbutamol (a β2 agonist), we thought to extend the concept to antimuscarinic agent as glycopyrronium.
AMAs are noted to act better in COPD. In our observation, the add-on glycopyrronium effect has been appreciated in both asthma and COPD. So far, there has been no test to identify the bronchodilator response to an AMA prospectively in obstructive airway diseases. Very recently, GOLD has mentioned the response to “short-acting anticholinergic” (possibly referring to ipratropium) in spirometry for diagnosis of COPD without any discussion or reference to it.
The cholinergic influence in airway obstruction is not asthma or COPD specific. The cholinergic nervous system controls several airway functions as airway smooth muscle contraction, inflammation, mucus secretion, and vasodilatation. It contributes to airflow obstruction in both asthma and COPD. Some asthmatics display high parasympathetic (cholinergic) tone. Antimuscarinic agents have been used in asthma and are listed in the treatment with severe cases and in poor control of the disease. In a recent randomized trial, glycopyrronium has been found safe and effective in mild to moderate persistent asthma. In COPD on the other hand, several positive effects are observed with different AMAs as ipratropium, oxitropium, tiotropium, and aclidinium.,,, Glycopyrronium is found safe and effective as a long-acting anticholinergic agent in several COPD trials.,,, It is found superior to tiotropium and it acts well in a combination of indacaterol, a LABA.,
The idea of testing the reversibility with glycopyrronium came from the knowledge of its rapid onset of action (6.1 ± 2.1 minutes) that is five times faster than that of tiotropium (29.4 ± 4.2 minutes) for inhibition of methacholine-induced calcium release. In GLOW1 study, a single dose of glycopyrronium to improve the mean FEV1 by 93 ml at 5 minutes and 144 ml at 15 minutes compared to placebo. In GLOW2 study, the change in FEV1 was 87 and 143 ml at 5 and 15 minutes after inhalation of glycopyrronium, whereas the same for tiotropium were 45 ml at 5 minutes and 78 ml at 15 minutes compared to placebo.
The reason for choosing 50 µg dose glycopyrronium was incidental because it is the only strength available in the Indian market. The quantity of the glycopyrronium moiety present in such capsule corresponds to a delivered dose of 44 µg once daily. Such dose has been used and found well tolerated and beneficial in moderate-to-severe COPD in Phase II clinical studies.,,,
Our observation provides us with an opportunity for pretreatment identification of a glycopyrronium responsive candidate. which may be of use in understanding individualized treatment in the future. This pilot observation is weak for the scanty number and having no disease-specific protocol or any severity specific response assessment. Despite that, the result supports that the two mechanisms of bronchodilatation with the use of adrenergic β2 agonist and cholinergic antagonists are different in obstructive disease. It will be interesting to identify the clinical characteristics of the responders. The patients were all essentially symptomatic suggesting possible not optimally controlled disease for both asthma and COPD. The acute effect of glycopyrronium needs to be assessed separately in different subsets of obstructive airway disease. There is a clue that glycopyrronium acts better I Thus, one may find the role of AMA in the future.
The degree of response may vary on several other factors including the clinical phenotype, the status of remodeling, concomitant use of other medications including anti-inflammatory drugs, co-existence of structural abnormalities as bronchiectasis, infection, and continuation of the exposure to noxious agents. One needs to look for the contribution of such elements too in the process.
We do not know the exact synergism or antagonism of the AMAs with β2 agonists as far as the immediate effects are concerned. The use of salbutamol may have reduced the independent impact of glycopyrronium. Therefore, repeating the same exercise of reversibility on the next morning with glycopyrronium first followed by salbutamol may be a worthwhile exercise to assess the independent impact of the LAMA in airway disease. To bring in a practice of doing “glycopyrronium reversibility” needs widespread systematic validation.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Vogelmeier CF, Criner GJ, Martinez FJ et al.
Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease2017 report. GOLD executive summary. Am J Respir Crit Care Med 2017;195:557-82.
Tashkin DP, Gross NJ. Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease. Int J COPD 2018;13:1873.
Oba Y, Keeney E, Ghatehorde N, Dias S. Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis. Cochrane Database Syst Rev 2018;12:CD012620.
Sechaud S, Machineni S, Tillmann H-C et al.
Pharmacokinetics of glycopyrronium following repeated once-daily inhalation in healthy Chinese subjects. Eur J Drug Metab Pharmacokinet 2016;41:723-31.
Kerwin E, Hébert J, Korenblat P et al.
Efficacy and safety of NVA237 versus placebo and tiotropium in patients with moderate-to-severe COPD over 52 weeks: the GLOW2 study. Eur Respir J 2012;40:1106-14.
Miller MR. ATS/ERS task force: standardisation of spirometry. Eur Respir J 2005;26:319-38.
Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma–summary report 2007. J Allergy Clin Immunol 2007;120:S94-138.
Rabe KF, Hurd S, Anzueto A et al.
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532-55.
Singh D, Agusti A, Anzueto A, Barnes et al.
Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019. Eur Respir J 2019;53.
Buels KS, Fryer AD. Muscarinic receptor antagonists: effects on pulmonary function. In Fryer AD, Christopoulos A, Nathanson NM, eds. Muscarinic Receptors. Berlin, Heidelberg: Springer 2012. p. 317-41.
Liccardi G, Salzillo A, Calzetta L et al.
Can bronchial asthma with an highly prevalent airway (and systemic)vagal tone be considered an independent asthma phenotype? Possiblerole of anticholinergics. Respir Med 2016;117:150-3.
Quirce S, Domínguez-Ortega J, Barranco P. Anticholinergics for treatment of asthma: review. J Investig Allergol Clin Immunol 2015;25:84-93.
Kerwin E, Wachtel A, Sher L et al.
Efficacy, safety, and dose response of glycopyrronium administered by metered dose inhaler using co-suspension delivery technology in subjects with intermittent or mild-to-moderate persistent asthma: A randomized controlled trial. Respir Med 2018;139:39-47.
Appleton S, Jones T, Poole P et al.
Ipratropium bromide versus long‐acting beta‐2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006;2006:CD006101.
Melani AS. Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol 2015;8:479-501.
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.
Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2014;2014.
D’Urzo A, Ferguson GT, van Noord JA et al.
Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res 2011;12:156.
D’Urzo A. Role of once-daily glycopyrronium bromide (NVA237) in the management of COPD. Ther Clin Risk Manag 2013;9:341.
Chapman KR, Beeh KM, Beier J et al.
A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med 2014;14:1-1.
Vincken W, Aumann J, Chen H, Henley M, McBryan D, Goyal P. Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study. Int J Chron Obstruct Pulmon Dis 2014;9:215-28.
Mahler DA, Decramer M, D’Urzo A et al.
Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J 2014;43:1599-609.
Wedzicha JA, Decramer M, Ficker JH et al.
Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1:199-209.
D’Urzo T, Ferguson G, Martin C et al.
P253 NVA237 once daily offers rapid and clinically meaningful bronchodilation in COPD patients that is maintained for 24 h: the GLOW1 trial. Thorax 2011;66(Suppl 4):A170-.
D’Urzo A, Ferguson GT, van Noord JA et al.
Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res 2011;12:1-3.
Kerwin E, Hébert J, Gallagher N et al.
Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J 2012;40:1106-14.
Arievich H, Overend T, Renard D et al.
A novel model-based approach for dose determination of glycopyrronium bromide in COPD. BMC Pulm Med 2012;12:1-2.
Fogarty C, Hattersley H, Di Scala L, Drollmann A. Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients. Respir Med 2011;105:337-42.
Verkindre C, Fukuchi Y, Flémale A et al.
Sustained 24-h efficacy of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Respir Med 2010;104:1482-9.
Vogelmeier C, Verkindre C, Cheung D et al.
Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Pulm Pharmacol Ther 2010; 23:438-44.