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Advances in Therapy Oct 2023Clinical studies demonstrate an accelerated decline in lung function in patients with moderate chronic obstructive pulmonary disease (COPD) (Global Initiative for...
INTRODUCTION
Clinical studies demonstrate an accelerated decline in lung function in patients with moderate chronic obstructive pulmonary disease (COPD) (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grade 2) versus severe and very severe COPD (GOLD grades 3 and 4). This predictive modelling study assessed the impact of initiating pharmacotherapy earlier versus later on long-term disease progression in COPD.
METHODS
The modelling approach used data on decline in forced expiratory volume in 1 s (FEV) extracted from published studies to develop a longitudinal non-parametric superposition model of lung function decline with progressive impact of exacerbations from 0 per year to 3 per year and no ongoing pharmacotherapy. The model simulated decline in FEV and annual exacerbation rates from age 40 to 75 years in COPD with initiation of long-acting anti-muscarinic antagonist (LAMA)/long-acting beta-agonist (LABA) (umeclidinium (UMEC)/vilanterol (VI)) or triple (inhaled corticosteroid (ICS)/LAMA/LABA; fluticasone furoate (FF)/UMEC/VI) therapy at 40, 55 or 65 years of age.
RESULTS
Model-predicted decline in FEV showed that, compared with 'no ongoing' therapy, initiation of triple or LAMA/LABA therapy at age 40, 55 or 65 years preserved an additional 469.7 mL or 236.0 mL, 327.5 mL or 203.3 mL, or 213.5 mL or 137.5 mL of lung function, respectively, by the age of 75. The corresponding average annual exacerbation rates were reduced from 1.57 to 0.91, 1.06 or 1.23 with triple therapy or to 1.2, 1.26 and 1.4 with LAMA/LABA therapy when initiated at 40, 55 or 65 years of age, respectively.
CONCLUSIONS
This modelling study suggests that earlier initiation of LAMA/LABA or triple therapy may have positive benefits in slowing disease progression in patients with COPD. Greater benefits were demonstrated with early initiation therapy with triple versus LAMA/LABA.
Topics: Humans; Adult; Middle Aged; Aged; Bronchodilator Agents; Adrenergic beta-2 Receptor Agonists; Administration, Inhalation; Pulmonary Disease, Chronic Obstructive; Disease Progression; Adrenal Cortex Hormones; Fluticasone; Muscarinic Antagonists; Drug Combinations
PubMed: 37382864
DOI: 10.1007/s12325-023-02583-1 -
The Cochrane Database of Systematic... Nov 2016Management of chronic obstructive pulmonary disease (COPD) commonly involves long-acting bronchodilators including beta-agonists (LABA) and muscarinic antagonists... (Review)
Review
BACKGROUND
Management of chronic obstructive pulmonary disease (COPD) commonly involves long-acting bronchodilators including beta-agonists (LABA) and muscarinic antagonists (LAMA). In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used. LABA and LAMA bronchodilators are now available in single combination inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers remains unclear.
OBJECTIVES
To assess the effect of adding an inhaled corticosteroid (ICS) to combination long-acting beta₂-agonist (LABA)/long-acting muscarinic antagonist (LAMA) inhalers for the treatment of stable COPD.
SEARCH METHODS
We carried out searches using the Cochrane Airways Group Specialised Register of Trials (searched 20 September 2016), Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 12) in the Cochrane Library (searched 15 December 2015) and MEDLINE (searched 15 December 2015). We also searched ClinicalTrials.gov, World Health Organisation (WHO) trials portal and pharmaceutical company clinical trials' databases up to 7 Janurary 2016.
SELECTION CRITERIA
We included parallel-group, randomised controlled trials (RCTs) of three weeks' duration or longer which compared treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We identified a total of 586 records in our search. Following removal of duplicates, 386 abstracts were assessed for inclusion. Six studies were identified as potentially relevant; however, all failed to meet the inclusion criteria on full-text assessment or after contacting the corresponding author to clarify study characteristics.
AUTHORS' CONCLUSIONS
There are currently no studies published assessing the effect of ICS in addition to combination LABA/LAMA inhalers for the treatment of stable COPD. As combination LABA/LAMA inhalers are now widely available, there is a need for well-designed RCTs to investigate whether ICS provides any added therapeutic benefit.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive
PubMed: 27830584
DOI: 10.1002/14651858.CD011600.pub2 -
Drug Metabolism and Pharmacokinetics 2013This study was designed to update the population pharmacokinetic model and investigate the exposure-response (efficacy and safety) and concentration-QT relationships for...
This study was designed to update the population pharmacokinetic model and investigate the exposure-response (efficacy and safety) and concentration-QT relationships for imidafenacin, a synthetic orally active muscarinic receptor antagonist. The population pharmacokinetic model was updated using data from 90 healthy subjects and 852 patients with an overactive bladder. Plasma concentration data from nine clinical studies were used, including new data from a long-term dose escalation study. The updated population pharmacokinetic model for imidafenacin adequately described the plasma concentration profile. The results were generally consistent with those obtained from the previous population pharmacokinetic analysis, indicating that no new covariates were found to influence the pharmacokinetics of imidafenacin. Exposure-response relationships in the long-term dose escalation study were investigated using a regression analysis with efficacy and safety endpoints as dependent variables. There was no clear relationship between exposure and any endpoint. The concentration-QT relationship was also evaluated to assess whether imidafenacin prolonged the concentration-dependent QT interval. There was no clear relationship between the plasma concentration of imidafenacin and QTc, indicating that concentration-dependent QTc interval prolongation was not observed.
Topics: Adult; Aged; Aged, 80 and over; Asian People; Demography; Female; Humans; Imidazoles; Male; Middle Aged; Muscarinic Antagonists; Urinary Bladder, Overactive
PubMed: 23089801
DOI: 10.2133/dmpk.dmpk-12-rg-062 -
NPJ Primary Care Respiratory Medicine Nov 2020The Global Initiative for Asthma recommends a stepwise approach to adjust asthma treatment to the needs of individual patients; inhaled corticosteroids (ICS) remain the... (Comparative Study)
Comparative Study Review
The Global Initiative for Asthma recommends a stepwise approach to adjust asthma treatment to the needs of individual patients; inhaled corticosteroids (ICS) remain the core pharmacological treatment. However, many patients remain poorly controlled, and evidence-based algorithms to decide on the best order and rationale for add-on therapies are lacking. We explore the challenges of asthma management in primary care and review outcomes from randomised controlled trials and meta-analyses comparing the long-acting muscarinic antagonist (LAMA) tiotropium with long-acting β-agonists (LABAs) or leukotriene receptor antagonists (LTRAs) as add-on to ICS in patients with asthma. In adults, LAMAs and LABAs provide a greater improvement in lung function than LTRAs as add-on to ICS. In children, results were positive and comparable between therapies, but data are scarce. This information could aid decision-making in primary care, supporting the use of add-on therapy to ICS to help improve lung function, control asthma symptoms and prevent exacerbations.
Topics: Adrenergic beta-2 Receptor Agonists; Adult; Anti-Asthmatic Agents; Asthma; Child; Delayed-Action Preparations; Drug Therapy, Combination; Humans; Leukotriene Antagonists; Muscarinic Antagonists; Primary Health Care; Tiotropium Bromide
PubMed: 33177503
DOI: 10.1038/s41533-020-00205-9 -
Drugs in R&D Sep 2015GSK961081 (batefenterol) is a novel bifunctional molecule composed of a muscarinic antagonist and a β2-agonist. The aims of this substudy were (1) to characterize the... (Randomized Controlled Trial)
Randomized Controlled Trial
Population Pharmacokinetics and Pharmacodynamics of GSK961081 (Batefenterol), a Muscarinic Antagonist and β2-Agonist, in Moderate-to-Severe COPD Patients: Substudy of a Randomized Trial.
GSK961081 (batefenterol) is a novel bifunctional molecule composed of a muscarinic antagonist and a β2-agonist. The aims of this substudy were (1) to characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of GSK961081 in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD); and (2) to investigate the relationship between systemic exposure to GSK961081 and key cardiac-related safety parameters. Three once-daily doses (100, 400, and 800 μg) and three twice-daily doses (100, 200, and 400 μg) of GSK961081 DISKUS were investigated. A two-compartment disposition PK model with first-order absorption adequately described the plasma GSK961081 concentration-time data. An empirical maximum-effects PD model adequately described the forced expiratory volume in 1 s (FEV1) response relationship with the covariate baseline FEV1 on day 1. No clear relationships between GSK961081 plasma drug levels and cardiac-related safety parameters were apparent. The PK and PD models will be used to guide the dose selection and development of GSK961081 in patients with COPD.
Topics: Adrenergic beta-2 Receptor Agonists; Adult; Aged; Carbamates; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones
PubMed: 26286203
DOI: 10.1007/s40268-015-0104-x -
International Journal of Chronic... 2017Long-term maintenance therapy for COPD is evolving rapidly. Dual bronchodilation with new long-acting muscarinic antagonist and long-acting beta-agonist (LAMA/LABA)... (Review)
Review
Long-term maintenance therapy for COPD is evolving rapidly. Dual bronchodilation with new long-acting muscarinic antagonist and long-acting beta-agonist (LAMA/LABA) fixed dose combination inhalers were introduced over the past 2 years. In clinical trials, these inhalers significantly improved lung function (trough forced expiratory volume in 1 second), patient-reported outcomes, and quality of life measures compared with placebo, their respective monocomponents, and tiotropium. The recorded adverse events of these new inhalers were also similar to those of their monocomponents or placebo. There are concerns regarding long-term complications (weight gain, osteoporosis, cataract) and increased risk of community-acquired pneumonia with the use of inhaled corticosteroids (ICS). The new LAMA/LABA inhalers could potentially reduce the use of ICS as part and parcel of maintenance therapy in COPD. Recent studies compared these LAMA/LABA inhalers with ICS/LABA combination inhalers in moderate-to-severe COPD. The results are promising and favor the LAMA/LABA inhalers, especially in the longer duration trials. Furthermore, there is a clearer picture emerging as to the subgroup of COPD patients who may be able to successfully switch from their current ICS/LABA therapy to these new LAMA/LABA inhalers.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Disease Progression; Drug Combinations; Forced Expiratory Volume; Humans; Lung; Maintenance Chemotherapy; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Time Factors; Treatment Outcome
PubMed: 28694698
DOI: 10.2147/COPD.S138006 -
The Journal of Pharmacology and... Jul 2020Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes,...
Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M receptor-selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes dose-dependently (0.1%-10.0%) prevented tactile allodynia, thermal hypoalgesia, and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia, whereas withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 day/wk. Similar local effects were noted with the nonselective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies. SIGNIFICANCE STATEMENT: Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.
Topics: Administration, Topical; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Mice; Mice, Inbred C57BL; Muscarinic Antagonists; Peripheral Nervous System Diseases
PubMed: 32327528
DOI: 10.1124/jpet.120.265447 -
Therapeutic Advances in Respiratory... Apr 2016A number of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) for treatment of moderate-to-very severe chronic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A number of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) for treatment of moderate-to-very severe chronic obstructive pulmonary disease (COPD) have recently become available, but none have been directly compared in head-to-head randomized controlled trials (RCTs). The purpose of this study was to assess the relative clinical benefit of all currently available LAMA/LABA FDCs using a Bayesian network meta-analysis (NMA).
METHODS
A systematic literature review identified RCTs investigating the efficacy, safety and quality of life associated with licensed LAMA/LABA FDCs for the treatment of moderate-to-very severe COPD. RCTs were screened for inclusion in the NMA using prespecified eligibility criteria. Data were extracted for outcomes of interest, including change in trough forced expiratory volume in 1 second (tFEV1) from baseline, St. George Respiratory Questionnaire (SGRQ) percentage of responders, Transition Dyspnea Index (TDI) percentage of responders, change in SGRQ score from baseline, change in TDI focal score from baseline, moderate-to-severe exacerbations, all-cause discontinuation, and discontinuation due to adverse events.
RESULTS
Following screening, a total of 27 trials from 26 publications with 30,361 subjects were eligible for inclusion in the NMA. Nonsignificant results were seen in most analyses comparing efficacy, exacerbations and discontinuation rates of included LAMA/LABA FDCs (i.e. aclidinium/formoterol 400/12 µg, glycopyrronium/indacaterol 110/50 µg, tiotropium + olodaterol 5/5 µg, umeclidinium/vilanterol 62.5/25 µg). Meta-regression controlling for post-bronchodilator percentage of tFEV1 predicted at baseline as well as meta-regression adjusting for concomitant use of inhaled corticosteroids at baseline was performed to assess the magnitude of effect modification and produced similar results as observed in the base case analysis.
CONCLUSION
All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making.
Topics: Adrenergic beta-2 Receptor Agonists; Bayes Theorem; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Lung; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Time Factors; Treatment Outcome
PubMed: 26746383
DOI: 10.1177/1753465815624612 -
Respirology (Carlton, Vic.) Oct 2017Several long-acting bronchodilators have been developed and are widely used as first-line treatment in patients with stable chronic obstructive pulmonary disease (COPD).... (Meta-Analysis)
Meta-Analysis Review
Several long-acting bronchodilators have been developed and are widely used as first-line treatment in patients with stable chronic obstructive pulmonary disease (COPD). However, the initial choice of therapy is still uncertain. The aim of this study was to examine the clinical efficacy and safety of long-acting muscarinic antagonist (LAMA) and long-acting beta2-agonist (LABA) in patients with stable COPD. We searched several databases and manufacturers' websites to identify relevant randomized clinical trials for meta-analysis. Outcomes of interest were trough forced expiratory volume in 1 s (FEV ), acute exacerbations, transitional dyspnoea index (TDI) score, St George's Respiratory Questionnaire (SGRQ) score and adverse events. Sixteen trials with a total of 22 872 patients were included in this study. Compared with LABA, LAMA were associated with a greater reduction in acute exacerbations (OR: 0.84, 95% CI: 0.74-0.94, P = 0.003) and fewer adverse events (OR: 0.92, 95% CI: 0.86-0.97, P = 0.005). There were no significant differences in trough FEV , TDI and SGRQ scores. In patients with stable COPD, LAMA were associated with a greater reduction in acute exacerbations and fewer adverse effects compared with LABA.
Topics: Adrenergic beta-2 Receptor Agonists; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Treatment Outcome
PubMed: 28654201
DOI: 10.1111/resp.13100 -
International Journal of Chronic... 2023Selection of treatments for patients with chronic obstructive pulmonary disease (COPD) may impact clinical outcomes, healthcare resource use (HCRU) and direct healthcare...
Treatment Patterns, Healthcare Utilization and Clinical Outcomes of Patients with Chronic Obstructive Pulmonary Disease Initiating Single-Inhaler Long-Acting β-Agonist/Long-Acting Muscarinic Antagonist Dual Therapy in Primary Care in England.
PURPOSE
Selection of treatments for patients with chronic obstructive pulmonary disease (COPD) may impact clinical outcomes, healthcare resource use (HCRU) and direct healthcare costs. We aimed to characterize these outcomes along with treatment patterns, for patients with COPD following initiation of single-inhaler long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) dual therapy in the primary care setting in England.
PATIENTS AND METHODS
This retrospective cohort study used linked primary care electronic medical record data (Clinical Practice Research Datalink-Aurum) and secondary care administrative data (Hospital Episode Statistics) in England to assess outcomes for patients with COPD who had a prescription for one of four single-inhaler LAMA/LABA dual therapies between 1st June 2015-31st December 2018 (indexing period). Outcomes were assessed during a 12-month follow-up period from the index date (date of earliest prescription of a single-inhaler LAMA/LABA within the indexing period). Incident users were those without previous LAMA/LABA dual therapy prescriptions prior to index; this manuscript focuses on a subset of incident users: non-triple therapy users (patients without concomitant inhaled corticosteroid use at index).
RESULTS
Of 10,991 incident users included, 9888 (90.0%) were non-triple therapy users, indexed on umeclidinium/vilanterol (n=4805), aclidinium/formoterol (n=2109), indacaterol/glycopyrronium (n=1785) and tiotropium/olodaterol (n=1189). At 3 months post-index, 63.3% of non-triple therapy users remained on a single-inhaler LAMA/LABA, and 22.1% had discontinued inhaled therapy. Most patients (86.9%) required general practitioner consultations in the first 3 months post-index. Inpatient stays were the biggest contributor to healthcare costs. Acute exacerbations of COPD (AECOPDs), adherence, time-to-triple therapy, time-to-first on-treatment moderate-to-severe AECOPD, time-to-index treatment discontinuation, HCRU and healthcare costs were similar across indexed therapies.
CONCLUSION
Patients initiating treatment with single-inhaler LAMA/LABA in primary care in England were unlikely to switch treatments in the first three months following initiation, but some may discontinue respiratory medication. Outcomes were similar across indexed treatments.
Topics: Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Adrenergic beta-2 Receptor Agonists; Nebulizers and Vaporizers; Drug Combinations; Administration, Inhalation; Patient Acceptance of Health Care; Primary Health Care; Bronchodilator Agents; Adrenal Cortex Hormones
PubMed: 36908830
DOI: 10.2147/COPD.S389281