Role of indacaterol,a once-daily bronchodilator,in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction that can lead to lung destruction and dyspnea. Although there has been a slight reduction in mortality in recent decades, COPD is still a serious health problem that has enormous costs and utilizes significant medical resources. There have been a number of pharmacologic interventions that have been developed for the treatment of COPD. Current guidelines recommend the use of long-acting bronchodilators for the treatment of moderate and severe stage COPD, since they have been shown to improve lung function, respiratory symptoms, and quality of life. Indacaterol is a once-daily beta2-agonist (β2-agonist) delivered by a single-dose dry powder inhaler used for the treatment of COPD. It is currently approved at a dose of 75 μg in the United States and a dose of 150 μg with a maximal dose of 300 μg in Europe and other countries. Several studies show that indacaterol was statistically superior to both long-acting β2-agonist, formoterol and salmeterol, as well as, noninferior to tiotropium. Indacaterol is generally well tolerated and has a good safety profile. Other studies show that there is an additive bronchodilator response with the addition of indacaterol to tiotropium, which would provide a once-daily treatment option for patient with moderate to severe COPD. This review discusses the pharmacokinetic, comparative efficacy and safety data for indacaterol.KEYWORDS : Indacaterol, chronic obstructive pulmonary disease (COPD), long-acting beta2-agonist (β2-agonist), tiotropium, salmeterol, formoterol, bronchodilator     

The role of long-acting bronchodilators in the management of stable COPD

Bronchodilators form the foundation of symptomatic treatment of COPD. Several long-acting bronchodilators are now available for use in COPD, but publications of large-scale studies of their efficacy have, for the most part, postdated the publication of major clinical guidelines. This article provides a critical review of large (> or =50 patients), double-blind, clinical trials of three long-acting bronchodilators in COPD (the once-daily anticholinergic tiotropium, and the twice-daily beta(2)-agonists formoterol and salmeterol) within the context of the objectives of treatment defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Fourteen published studies were identified, of which 12 studies were published since the release of the GOLD guidelines. All three long-acting bronchodilators were found to effectively improve lung function; however, they differed in their effects on outcomes other than bronchodilation, with salmeterol demonstrating inconsistent efficacy compared with placebo in preventing exacerbations and improving health status, and only tiotropium demonstrating consistent superiority to the short-acting bronchodilator ipratropium. Based on this review, a treatment algorithm for the introduction of long-acting bronchodilators to patients with COPD is proposed, which includes the use of long-acting bronchodilators early in the treatment algorithm.     

The Role of Fixed-Dose Dual Bronchodilator Therapy in Treating COPD

The incidence of chronic obstructive pulmonary disease (COPD) is rising in the United States, and the disease represents a significant source of morbidity and mortality. Primary care providers face many challenges in COPD diagnosis and treatment, as different clinical phenotypes require personalized treatment approaches. Patient adherence and inhaler technique also contribute to treatment outcomes. Around 48% of primary care providers are unaware of guidelines and recommendations for COPD diagnosis and treatment, which may lead to misdiagnosis or undertreatment of COPD symptoms. Inadequately treated COPD can impair patients' quality of life and ability to perform everyday activities. Long-acting bronchodilator therapy is the cornerstone treatment for patients with COPD; combinations of bronchodilators of different pharmacological classes have shown improved efficacy vs monotherapy. We review the rationale behind fixed-dose dual bronchodilator therapy, evidence for the 4 currently Food and Drug Administration-approved long-acting anticholinergic bronchodilators/long-acting β₂-agonists fixed combinations, patient suitability for the available inhaler devices, and practical guidance to optimize personalized care for patients with COPD.     

Profiling the bronchodilator effects of the novel ultra-long-acting β2-agonist indacaterol against established treatments in chronic obstructive pulmonary disease

Indacaterol is a novel, inhaled, ultra-long-acting β(2)-agonist providing 24-h bronchodilation with once-daily (od) dosing for maintenance use in patients with chronic obstructive pulmonary disease (COPD). This article reviews the bronchodilator properties of indacaterol compared with other treatments used in COPD. Data from five published placebo-controlled studies were reviewed. Two 14-day crossover studies, the first comparing indacaterol 300 μg od with salmeterol 50 μg twice daily (bid), the second comparing indacaterol 150 μg and 300 μg od with tiotropium 18 μg od, assessed forced expiratory volume in 1 s (FEV(1)) at 24 h postdose (trough). Third, a 14-day crossover study evaluated trough FEV(1) following indacaterol 300?μg dosed morning or evening compared with salmeterol 50 μg bid. Fourth, a single-dose study of indacaterol 150 and 300 μg measured FEV(1) at 5 min postdose compared with salmeterol/fluticasone 50/500 μg and salbutamol 200 μg. Finally, data from a 1-year study with indacaterol 300 μg and formoterol 12 μg bid were examined to determine whether bronchodilation was maintained long term. In the first two studies, indacaterol increased trough FEV(1) after 14 days by a statistically significant and clinically relevant margin over placebo; indacaterol had a greater effect than salmeterol and a similar effect to tiotropium. In the third study, indacaterol had the same effect on trough FEV(1) whether dosed in the morning or evening. In the fourth study, the onset of the bronchodilator effect of indacaterol was similar to that of salbutamol. In the fifth study, the bronchodilator effect of indacaterol on trough FEV(1) was maintained at a significant and clinically relevant level over 52 weeks, whereas the bronchodilator effect of formoterol diminished over time. To conclude, indacaterol is a highly effective bronchodilator that is superior to or at least as effective as other available long-acting bronchodilators for COPD.     

The role of indacaterol for chronic obstructive pulmonary disease (COPD)

Indacaterol is the first long-acting β2-agonist (LABAs) approved for the treatment of chronic obstructive pulmonary disease (COPD) that allows for once-daily (OD) administration. It is rapidly acting, with an onset of action in 5 minutes, like salbutamol and formoterol but with a sustained bronchodilator effect, that last for 24 hours, like tiotropium. In long-term clinical studies (12 weeks to 1 year) in patients with moderate to severe COPD, OD indacaterol 150 or 300 μg improved lung function (primary endpoint) significantly more than placebo, and improvements were significantly greater than twice-daily formoterol 12 μg or salmeterol 50 μg, and noninferior to OD tiotropium bromide 18 μg. Indacaterol was well tolerated at all doses and with a good overall safety profile. Cost-utility analyses show that indacaterol 150 μg has lower total costs and better outcomes than tiotropium and salmeterol. These findings suggest that indacaterol can be considered a first choice drug in the treatment of the patient with mild/moderate stable COPD. However, in people with COPD who remain symptomatic on treatment with indacaterol, adding a long-acting muscarinic antagonist (LAMA) is the preferable option. In any case, it is advisable to combine indacaterol with a OD inhaled corticosteroid (ICS), such as mometasone furoate or ciclesonide, in patients with low FEV1, and, in those patients who have many symptoms and a high risk of exacerbations, to combine it with a LAMA and a OD ICS.KEY WORDS : Long-acting β2-agonists (LABAs), indacaterol, chronic obstructive pulmonary disease (COPD), combination therapy     

A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison

This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled beta2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV(1)40% of predicted and > or =1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400microg or placebo via multi-dose dry powder inhaler, or indacaterol 400microg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18microg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC(22-24h)) on Day 1. Clinically relevant improvements versus placebo in FEV1 AUC(22-24h) were seen for 400 and 200microg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200microg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension. The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled beta2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile.     

新一代超长效支气管扩张剂——茚达特罗

茚达特罗是新一代超长效β2受体激动剂.大量的临床前试验及临床试验证实茚达特罗起效迅速,在体内5 min即可产生支气管舒张效应,作用持续时间长达24 h,每日只需用药一次即能良好控制慢性阻塞性肺疾病和支气管哮喘患者喘息症状及改善肺功能.另外,茚达特罗引起的全身系统不良反应少,程度轻微,是治疗慢性阻塞性肺疾病和支气管哮喘的理想药物.     

Is a long-acting inhaled bronchodilator the first agent to use in stable chronic obstructive pulmonary disease?

PURPOSE OF REVIEW: This article reviews findings from recently published randomized controlled clinical trials to address the question whether a long-acting inhaled bronchodilator should be the initial choice for maintenance therapy in patients with stable, symptomatic chronic obstructive pulmonary disease (COPD). RECENT FINDINGS: Results of recent clinical trials suggest that a long-acting inhaled bronchodilator, either once-daily tiotropium or twice-daily salmeterol or formoterol, has advantages over a regularly-scheduled short-acting anticholinergic inhaled bronchodilator (ipratropium) as initial maintenance therapy in patients with at least moderate, stable, symptomatic COPD (forced expired volume in 1 second 相似文献   

The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting β₂-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.     

The Role of Tiotropium Bromide,a Long-Acting Anticholinergic Bronchodilator,in the Management of COPD

Bronchodilator therapy forms the mainstay of treatment for symptomatic patients with COPD. Long-acting bronchodilators, which maintain sustained airway patency over a 24-hour period, represent an advance in therapy. Tiotropium bromide is a new long-acting inhaled anticholinergic agent with superior pharmacodynamic properties compared with the short-acting anticholinergic, ipratropium bromide. Tiotropium bromide has been consistently shown to have a greater impact than ipratropium bromide on clinically important outcome measures such as health status. The mechanisms of clinical benefit with tiotropium bromide are multifactorial, but improved airway function, which enhances lung emptying and allows sustained deflation of over-inflated lungs, appears to explain improvements in dyspnea and exercise endurance in COPD. Inhaled tiotropium bromide therapy has also been associated with reduction in acute exacerbations of COPD as well as reduced hospitalizations. The safety profile of tiotropium bromide is impressive: dry mouth is the most common adverse event and rarely necessitates termination of the drug. No tachyphylaxis to tiotropium bromide has been demonstrated in clinical trials lasting up to 1 year. There is preliminary information that the combination of long-acting anticholinergics and long-acting beta2-adrenoceptor agonists provides additive physiological and clinical benefits. According to recent international guidelines, long-acting bronchodilators should be considered early in the management of symptomatic patients with COPD in order to achieve effective symptom alleviation and reduction in activity limitation. Tiotropium bromide, because of its once-daily administration and its established efficacy and tolerability profile, has emerged as an attractive therapeutic option for this condition.     

Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators

Chronic obstructive pulmonary disease (COPD) is a treatable disease characterized by progressive airflow limitation. Prevention of disease progression, improvement of symptoms, exercise tolerance, health status, and decrease in exacerbations and in mortality are the main goals of the management of COPD. Bronchodilators play a pivotal role in the treatment of symptomatic patients with COPD. Inhaled short-acting bronchodilators are currently recommended for rescue of symptoms in patients with mild disease, whereas inhaled long-acting bronchodilators are recommended as first-line agents for maintenance therapy in patients with moderate and severe disease and those with daily symptoms. Long-acting bronchodilators improve symptoms, exercise tolerance, and health status, and reduce exacerbations in patients COPD. However, their effects on long-term decline in lung function and mortality are currently under investigation. When symptoms are not sufficiently controlled by the use of one bronchodilator, combining bronchodilators of different classes may be a more effective approach. In fact, recent evidence supports the regular use of a combination of a long-acting beta2-adrenoceptor agonist and a long-acting anticholinergic agent in patients with severe COPD. Combining a long-acting beta2-adrenoceptor agonist with an inhaled corticosteroid has also been shown to be more effective than the use of either agent alone. The use of theophylline has declined in recent years because of its narrow therapeutic index, and should be reserved as a third-line option in patients with very severe disease. Several novel bronchodilators are now in different stages of development for use alone or in combination with other agents.     

Cost-utility analysis of indacaterol in Germany: A once-daily maintenance bronchodilator for patients with COPD

Introduction

Indacaterol is a novel inhaled once-daily long-acting beta₂-agonist (LABA) for the maintenance treatment of COPD that has been compared to existing inhaled monotherapies on a number of symptomatic endpoints in clinical studies. With constrained healthcare budgets, the objective of this analysis was to evaluate the cost-effectiveness of indacaterol 150 μg, the approved starting dose for maintenance therapy, from a German heath service perspective against the most widely used bronchodilator tiotropium, and the twice-daily LABA, salmeterol.

Methods

A Markov model was developed with the following main health states: Mild, Moderate, Severe, and Very Severe COPD, based on pre-bronchodilator FEV₁ measures reported in the indacaterol clinical trials, and death. Each disease severity health state had two associated health states for severe or non-severe exacerbation. The model considered patients with moderate to severe COPD, with a mean age of 64 years. The base case time horizon was three years, with discounting set at 3% for costs and benefits. Selected clinical inputs and health state utilities were derived from indacaterol clinical trials, while costs were based on publicly available drug prices and tariffs or published sources. Inputs describing disease progression were based on published data on the rate of FEV₁ decline.

Results

Point-estimates show that indacaterol 150 μg is dominant (lower total costs and better outcomes) against tiotropium and salmeterol. An alternative analysis comparing indacaterol 300 μg (maximum dose) against tiotropium, showed an incremental cost-effectiveness ratio (ICER) of approximately €28,300 per QALY.

Conclusion

Indacaterol is cost-effective compared to tiotropium and salmeterol.     

The scientific rationale for combining long-acting β2-agonists and muscarinic antagonists in COPD

Bronchodilators are the cornerstone of pharmacological management of COPD. For patients whose conditions are not sufficiently controlled by monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist with an inhaled β₂-agonist, seems a convenient way of delivering treatment and obtaining superior results. When administered as combination therapy, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. More recently, long-acting β₂-agonists (LABAs) and muscarinic antagonists (LAMAs) have been introduced, and current guidelines recommend regular use of these agents alone or as concurrent therapy in COPD to maximize bronchodilation. In particular, the combination of a LABA plus LAMA seems to play an important role. This article illustrates the scientific rationale for combining LABAs and LAMAs in COPD, reviews the clinical evidence to support these agents given in combination, and discusses their potential role in the management of patients with COPD.     

NVA237, a long-acting muscarinic antagonist, as an emerging therapy for chronic obstructive pulmonary disease

Bronchodilation with a long-acting muscarinic antagonist (LAMA) or long-acting β(2)-agonist is central to the management of chronic obstructive pulmonary disease (COPD). Tiotropium, the first LAMA available for use in COPD, has been shown to be an effective bronchodilator and is generally safe and well tolerated. However, tiotropium has limitations that include a high incidence of dry mouth, slow onset of action and, in some studies, a part of the patient population did not achieve clinically significant bronchodilation. It also remains unclear whether tiotropium reduces progressive deterioration of lung function in patients with COPD. An ideal LAMA would provide clinically meaningful bronchodilation, deliver symptom relief, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations and reduce mortality risk. A 24-h duration of action, rapid onset of action and a good safety and tolerability profile are also desirable. The once-daily LAMA, NVA237 (glycopyrronium bromide), may meet some of these characteristics. NVA237 has high selectivity for the muscarinic type-3 (M(3)) receptor which might potentially result in a higher therapeutic index than tiotropium, which is less selective for M(3). Phase II studies showed that NVA237 once daily provides clinically significant 24-h bronchodilation with a rapid onset of action and a favourable safety and tolerability profile. Phase III studies are ongoing that will assess the long-term safety and efficacy of NVA237.     

Pharmacologic rationale,efficacy and safety of the fixed-dose co-formulation of indacaterol and glycopyrronium

Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder, usually characterized by progressive and poorly reversible airflow limitation. Inhaled long-acting bronchodilators, namely LABA (long-acting β₂-adrenergic agonists) and LAMA (long-acting muscarinic receptor antagonists) are the mainstay of COPD treatment. Because the symptoms of many patients with COPD do not satisfactorily improve by using a single, either LABA or LAMA bronchodilator, the synergism of action resulting from the combination of the different bronchodilating mechanisms activated by LABA and LAMA, respectively, can significantly contribute to a better disease control. Based on these clinical and pharmacological considerations, several LABA/LAMA fixed-dose combinations have been developed and experimentally evaluated. Within such a context, the drug co-formulation containing indacaterol and glycopyrronium is probably the LABA/LAMA association which has been most extensively studied during the last few years.     

Future directions in the pharmacologic therapy of chronic obstructive pulmonary disease

Current therapy for chronic obstructive pulmonary disease (COPD) fails to alter its relentless progression. This remains a significant challenge and unmet need. A recent advance is the demonstration that treatment with a fixed dose of an inhaled corticosteroid and a long-acting beta2-agonist in COPD improves lung function and quality of life, and reduces exacerbation more effectively than either drug alone. Other improvements include the introduction of tiotropium, a once-daily anticholinergic. In advanced clinical development are other once-daily bronchodilators and combinations of anticholinergic drugs and beta2-agonists. Increased understanding of the pathogenesis of COPD has led to novel drugs aimed at inhibiting targets, including phosphodiesterase 4, proteases, and various inflammatory mediators. Furthermore, COPD is increasingly seen as a systemic disorder or, indeed, may be a pulmonary manifestation of a complex pathophysiologic response to chronic inhalation of toxic irritants and associated with aging. Future therapy may involve better understanding of how best to target existing drugs used to treat cardiovascular disorders associated with smoking, such as atherosclerosis and hypercoagulability, and the development of new drugs that target systemic and metabolic manifestations that either result from or coexist with chronic lung inflammation, hypoxia, and cardiovascular disease in COPD.     

Role of bronchodilators in chronic obstructive pulmonary disease

The prevalence of chronic obstructive pulmonary disease (COPD) continues to be on the rise. Bronchodilators are first line agents for the symptomatic management of this disease and have proven to be effective in both stable disease status and exacerbations. The stepwise escalation of therapy for COPD according to severity has been outlined in international guidelines. Different classes of bronchodilators exist. The most experience is available for short-acting beta-agonists and anticholinergics. These agents are mainly recommended for the treatment of mild COPD and for symptomatic patients on an as needed basis. Long-acting beta-agonists and anticholinergics have been developed more recently. They are more convenient to use for patients with advanced disease who require maintenance therapy with bronchodilators, and have been shown in this group of patients to provide superior efficacy compared with short-acting agents. Tiotropium, a long-acting anticholinergic, appears to be particularly powerful and may eventually replace ipratropium as the primary agent for COPD treatment. In contrast, the usage of theophylline, which used to be part of the mainstay of treatment for COPD, has declined, mainly secondary to a narrow therapeutic margin and side effects, but it is inexpensive and still has its role. New agents like phosphodiesterase-4-inhibitors are interesting substances that may become important adjuncts in COPD management, but there is limited experience so far. None of the bronchodilators have been shown to change outcome in COPD, but this issue is under active investigation.     

Drugs in clinical development for chronic obstructive pulmonary disease

Many drugs may be potentially useful in the treatment of chronic obstructive pulmonary disease (COPD), but relatively few become available for human use due to lack of safety, lack of efficacy, or both. This is an inherent risk in the drug development process, which coupled with the limited understanding of the molecular pathogenesis of COPD, has produced a trend toward improving existing compounds rather than to develop new compounds. This review focuses on improved existing compounds and newly discovered compounds that are in clinical trials, but not yet marketed. The improved existing compounds include: isomers of the long-acting bronchodilators, once-daily beta2-adrenoceptor agonists, anticholinergics and corticosteroids. The pool of novel compounds is in constant fluctuation and comprises anti-inflammatory drugs, antioxidants, leukotriene modifiers and a number of compounds aimed at treating different aspects of COPD such as pulmonary hypertension and hypophosphatemia.     

Die chronisch-obstruktive Lungenerkrankung (COPD)

Chronic obstructive pulmonary disease (COPD) is a very common chronic disease with increasing prevalence. Inhaled particles and gases (in particular tobacco smoke) induce chronic inflammation of the airways accompanied by a not fully reversible airflow limitation. Destruction of lung tissue and deterioration of gas exchange may follow. In parallel, several comorbidites can be observed. The COPD assessment was revised and now takes into account lung function, the patients’ symptoms, and history of exacerbations. More recently, several new long-acting bronchodilators received approval. Combination products, consisting of long-acting β2-agonists and long-acting anticholinergics, and a new combination of a long-acting β-agonist and an inhaled corticosteroid will follow in the near future. Smoking cessation is of central importance.     

Efficacy and safety of formoterol for the treatment of chronic obstructive pulmonary disease

Formoterol is a selective long-acting beta2-adrenergic receptor agonist (LABA) that provides significant and sustained bronchodilatory effect for up to 12h following a single dose. The onset of effect is significantly faster with formoterol compared with an alternative LABA, salmeterol, although both have a similar duration of action. The overall efficacy of formoterol in improving lung function and controlling symptoms of chronic obstructive pulmonary disease (COPD) is comparable to that of salmeterol and potentially superior to that of ipratropium or theophylline. Formoterol provides additional benefit when administered in combination with other bronchodilators or inhaled corticosteroids. In clinical studies, formoterol was well tolerated and had an adverse-event profile similar to that of other beta2-adrenergic receptor agonists. Formoterol is a rapidly acting, well-tolerated, effective beta2-adrenergic receptor agonist that can be regularly used as a long-acting bronchodilator for patients with moderate to severe COPD, as per recommendations of the current treatment guidelines.