CC BY
30
БЗОРЫ
© E. Puxxedu, J. Ora, L. Calzetta, M. Cazzola, 2017
УДК 616.24-036.12-085.234(048.8) DOI: 10.20969/VSKM.2017.10(1).7-14
PROGRESS AND PROSPECTS FOR LONG-ACTING ß2-AGONISTS IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
ERMANNO PUXXEDU, pneumologist, assistant of professor of the Department of respiratory medicine, the Department of systems medicine, University of Rome Tor Vergata, Rome, Italy, University Hospital Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy, e-mail: ERMANNOPUX@libero.it
JOSUEL ORA, pneumologist, University hospital Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy, e-mail: josuel78@gmail.com LUIGINO CALZETTA, D. Med. Sci., research worker of the laboratory of respiratory clinical pharmacology of the Department of systems medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy, e-mail: luigino.calzetta@uniroma2.it MARIO CAZZOLA, honorary professor of respiratory medicine, the Department of systems medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy, e-mail: mario.cazzola@uniroma2.it
Abstract. Aim. The treatment of chronic obstructive pulmonary disease (COPD) is generally based on the assumption of drug combinations in which ß2-agonists are commonly included. Ultra-LABAs were developed to induce a greater adherence to the treatment as a result of the simplification of treatment with the reduction of the daily dose to be taken. Material and methods. We analyzed the current literature data on ß2-adrenergic agonists. The potential positioning of ultra-LABAs in the treatment of COPD and their cardiovascular safety is discussed according to the new information on the topics. Results and discussion. The novel fixed-dose combinations of ultra-LABAs with LAMAs and/or ICSs are examined, as well as the novel ultra-LABAs under clinical development and the ultra-LABAs in preclinical development. Conclusion. The huge interest in developing new ultra-LABAs has apparently declined progressively in recent times. Nevertheless, ultra-LABAs are considered a fundamental component of the combinations with other classes of drugs (LAMAs and ICSs) that are central for treating COPD and now are administered on oncedaily basis. Key words: Cardiovascular safety; combination therapy; COPD; monotherapy; ultra-LABAs.
For reference: Puxxedu E, Ora J, Calzetta L, Cazzola M. Progress and prospects for long-acting ß2-agonists in the treatment of COPD. The Bulletin of Contemporary Clinical Medicine. 2017; 10 (1): 7—14. DOI: 10.20969/ VSKM.2017.10(1).7-14.
ДОСТИЖЕНИЯ И ПЕРСПЕКТИВЫ ПРИМЕНЕНИЯ р2-АГОНИСТОВ ДЛИТЕЛЬНОГО ДЕЙСТВИЯ В ЛЕЧЕНИИ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНИ ЛЕГКИХ (ХОБЛ)
ЕРМАННО ПУКСЕДДУ, пульмонолог, ассистент кафедры респираторной медицины, кафедра системной медицины, Университет Рима Тор Вергата, Рим, Италия, Университетская больница Тор Вергата, Виа Монпелье, 1, 00133, Рим, Италия, e-mail: ERMANNOPUX@libero.it
ЖОЗУЭЛ ОРА, пульмонолог, Университетская больница Тор Вергата, Виа Монпелье, 1, 00133, Рим, Италия, e-mail: josuel78@gmail.com
ЛУИДЖИНО КАЛЗЕТТА, докт. мед. наук, научный сотрудник лаборатории респираторной клинической фармакологии кафедры системной медицины, Университет Рима Тор Вергата, Виа Монпелье, 1, 00133, Рим, Италия, e-mail: luigino.calzetta@uniroma2.it
МАРИО КАЗЗОЛА, почетный профессор в области респираторной медицины, кафедра системной медицины, Университет Рима Тор Вергата, Виа Монпелье, 1, 00133, Рим, Италия, e-mail: mario.cazzola@uniroma2.it
Реферат. Цель. Лечение хронической обструктивной болезни легких (ХОБЛ), как правило, предполагает назначение комбинации лекарственных препаратов, одним из которых зачастую является агонист Р2-адренорецепторов. Данная статья написана с целью представления информации об агонистах Р2-адренорецепторов длительного действия (ultra-LABAs) — современной форме препаратов, обеспечивающей высокую приверженность пациентов лечению благодаря упрощенной схеме приема 1 раз в сутки. Материал и методы. Проанализированы современные литературные данные об агонистах Р2-адренорецепторов. В частности, новейшие данные о применении ultra-LABAs в лечении ХОБЛ, а также вопросы безопасности препарата для сердечно-сосудистой системы. Результаты и их обсуждение. Рассматривается инновационный метод назначения фиксированных доз LABAs в комбинации с антихолинергическими препаратами длительного действия (LAMAs) и/или с ингаляционными кортикостероидами, а также новейших препаратов ultra-LABAs, находящихся на этапах клинического исследования и доклинической разработки. Заключение. Интерес к разработке новых агонистов Р2-адренорецепторов длительного действия значительно снизился за последние годы. Тем не менее ultra-LABAs считаются одним из основных компонентов лечения ХОБЛ в комбинации с другими классами препаратов (LAMAs и ингаляционными кортикостероидами), которые в настоящее время находятся на этапе внедрения для регулярного использования.
Ключевые слова: безопасность сердечно-сосудистой системы, комбинированная терапия, ХОБЛ, монотерапия, ultra-LABAs.
Для ссылки: Progress and prospects for long-acting P2-agonists in the treatment of COPD / E. Puxxedu, J. Ora, L. Calzetta, M. Cazzola // Вестник современной клинической медицины. — 2017. — Т. 10, вып. 1. — С.7—14. DOI: 10.20969/VSKM.2017.10(1).7-14.
Introduction. In 2005, we coined the term ultra long-acting p2-agonists (ultra LABAs) to identify the novel p2-agonists that, at least from the pharmacological point of view, seemed able of inducing bronchodilation for 24 hours or more [1]. We pointed out that «the oncedaily dosing of a LABA would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes in patients with asthma and COPD». Apparently, at that time several ultra LABAs (arformoterol, carmoterol, indacaterol, GSK-159797 (milveterol), GSK-597901, GSK-159802, GSK-642444 (vilanterol) and GSK-678007) were under development.
In 2007, we highlighted that arformoterol was not a real once daily LABA and also stressed that «Any company planning to develop a new ultra-LABA must consider very carefully the pharmacological characteristics of the p2-adrenoceptor agonist component to understand how it will fit into current treatment strategies and whether it should be used only in combination with other drugs» [2].
In 2009, we included in the list of new p2-agonists under development BI-1744-CL (olodaterol), and LAS100977 (abediterol) [3]. Furthermore, we illustrated the possible development of saligenin- or indole-containing and adamantyl-derived p2-agonists and highlighted that despite this interesting profile of milveterol, it was likely that it would be developed only as a back-up because of the greater therapeutic index of vilanterol, and also the great delay in the development of carmoterol, although it was the oldest of the ultra-LABAs under investigation.
In 2011, considering the great interest within the pharmaceutical industry in the discovery of effective ultra LABAs, we described what we considered the mandatory pharmacological characteristics of any new LABA [4]. They included longer duration of action (compared with existing LABAs) with a true 24 h sustained bronchodilator efficacy allowing once daily dosing, fast onset of action, superior efficacy compared with existing LABAs, and favourable safety and tolerability profile.
At that time, indacaterol had already received European regulatory approval and been launched in several countries, whereas olodaterol, vilanterol, carmoterol, LAS100977 (abediterol) and PF-610355 were apparently under development.
In the 2012, in a review paper mainly focuses on bronchodilators that were in Phase I and II clinical trials, we described AZD3199, abediterol, and PF-610355 and pointed out that further development of this last ultra-LABA had been stopped [5].
In the 2013, in a further revision of the literature focused on p2-agonist treatment in lung disease [6], we highlighted that it was likely that the also the development of AZD3199had been discontinued for strategic and regulatory reasons.
In the last three years, apart from the publication of some of our original contributions focused primarily on understanding the value of dual bronchodilation [7-12], in which surely p2-agonists play a fundamental role, we examined and described the development of single ultra-LABAs now entered into the daily practice as monotherapy or in combination with a long-acting muscarinic antagonist (LAMA) or an inhaled corticosteroid (ICS) [13-21].
In this article, we aim to describe the novelties that have emerged in recent years on the use of p2-agonists in the treatment of COPD and illustrate the possible further development of this class of bronchodilators.
Positioning ultra-LABAs in the treatment
of COPD
Basically, almost all the new information on the topic has been obtained with indacaterol, which is the archetype of this new group of p2-agonists and is the first ultra-LABA approved for the treatment of COPD.
Since in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report no distinction is made as to which class of bronchodilators, either LABAs or LAMAs, should be considered first, but they only recommend the use of long-acting bronchodilator agents [22], Kerstjens and colleagues [23] examined the effectiveness of indacaterol and other bronchodilators compared with placebo in patients across the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 categories A to D through a post-hoc, subgroup pooled analysis of 6-month efficacy data from three randomized, placebo-controlled, parallel-group studies involving 3862 patients. The results indicated that indacaterol was effective in improving lung function, dyspnoea, and rescue medication use across all four GOLD categories. Furthermore, a pooled analysis of two randomized, parallel-group trials showed that in patients in GOLD categories A and B indacaterol improved lung function and provided a greater benefit in terms of dyspnoea and health status compared with placebo
[24]. However, a post hoc pooled analysis of four trials suggested that concomitant COPD therapies and COPD severity influenced the magnitude of the bronchodilatory effect of another ultra-LABA, olodaterol, in a subgroup of patients with moderate to severe disease (GOLD 2-3)
[25]. In particular, of the patients who had not received concomitant therapy, those who were GOLD stage 2 had FEV1 AUC0-3 and trough FEV1 responses with olodaterol that were 1.2- and 1.9-fold, respectively, higher than in, GOLD 3 patients. Anotherpost-hoc analysis of pooled data from clinical studies compared the efficacy of once daily inhaled bronchodilators indacaterol (150 and 300^g) and tiotropium (18^g) according to baseline breathlessness severity in patients with COPD documented that, while all treatments were equally effective in patients with less dyspnoea, indacaterol 300 ^g was preferable for patients with COPD who suffered from more severe dyspnoea [26].
The crucial Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/ Fluticasone to Indacaterol (INSTEAD) trial, which enrolled COPD patients with moderate airflow limitation and without a history of exacerbations in the previous year, but on treatment with ICS/LABA combination therapy for >3 months, documented that these patients can be switched from ICS/LABA to indacaterol 150 ^g with no efficacy loss [27].
Interestingly, a single-centre audit of a primary care COPD cohort comprising all patients treated with indacaterol for a minimum of 12 months, showed that indacaterol was an effective LABA as an escalation or switch medication from a LABA/ICS combination significantly reducing the number of exacerbations in patients with moderate-to-severe COPD [28].
This is an intriguing finding, but it must be admitted that to determine whether a treatment with ultra-LABAs is sufficient to prevent, or at least delay, exacerbations of COPD is quite difficult. In a pooled analysis of data from three randomized, double blind, placebo-controlled studies, both indacaterol doses, 150 and 300 ^g, were associated with significant reductions in exacerbations versus placebo [29]. However, the Indacaterol: providing opportunity to re-engage patients with life (INVIGORATE) study showed that tiotropium offered greater protection from exacerbations than indacaterol [30], but the absolute number of events was small and the difference between treatments was of uncertain clinical importance.
A post hoc analysis has shown that blood eosinophil count >2%, which is a promising biomarker of response to ICSs in patients with COPD [31], does not appear to predict bronchodilator response to p2-agonists in either ICS users or non-users [32].
It is remarkable to point out that a UK-based cost-utility analysis of indacateroldemonstrated that indacaterol can produce better outcomes at a lower cost to the healthcare system compared with both tiotropium and salmeterol and is likely to remain cost-effective under a range of assumptions [33]. In particular, the proportion of patients in each of the COPD stages and the mortality rate associated with very severe COPD are the variables with the largest impact on the results.
Cardiovascular safety of ultra-LABAs
All inhaled p2-agonists have a potential to increase heart rate and the incidence of ventricular arrhythmias in patients with COPD [6] because some of the p2-adrenoceptors in the atria and ventricles are p2, and thus even selective p2-agonists can provoke direct simulation of the heart [34, 35]. Furthermore, they can also induce vasodilation and reflex tachycardia as a consequence of the p2-adrenoceptors stimulation [34, 35].
A meta-analysis of randomized, double-blind, parallel-group, placebo-controlled trials for ultra-LABAs (and also formoterol and salmeterol) treatment of COPD with at least 3 months of follow-up suggested that inhaled LABAs significantly reduced the rate of fatal cardiovascular events in COPD patients compared with placebo and were able to significantly decrease fatal cardiovascular events in long-term, but not in the short-term, trials and in studies in which the predicted FEV1 of the participants were less than 50% [36].
Unsurprisingly, COPD patients with cardiac report a higher incidence of cardiovascular adverse events versus those with no history, but fortunately, no increase in risk estimates of fatal or any major adverse cardiac event (MACE) end points is observed in this subgroup and also in those who are taking p-blockers [37].
A recent study, which has investigated the ability of a chronic treatment with indacaterol to reverse cardiac remodelling and its effects on myocardial infarction in a rat model of heart failure, demonstrated that this ultra-LABA significantly reduced the infarct size in heart failure rats and BNP levels [38]. Intriguingly, the results of the study showed an additive interaction between indacaterol and metoprolol, a selective p1-adrenoceptor antagonist, in normalizing and reversing cardiac remodelling in this experimental model of heart failure. This emerging information suggests the need for more extensive studies with the combination of an ultra-LABA and a selective p1-adrenoceptor antagonist in patients suffering from both heart failure and COPD, considering that pharmacological modulation of p-adrenoceptor function is one of the critical issues in the treatment of these patients [39].
There is documentation that ultra-LABAs are able to induce a rapid reduction in BNP levels in patients admitted to emergency department for AECOPD [40]. It is not easy to explain why ultra-LABAs decrease BNP levels. The most plausible hypothesis is that they are able to directly influence the pulmonary hemodynamics. Alternatively, it has been suggested that ultra-LABAs are able to cause an attenuation of air trapping, leading to a reduction of intrathoracic pressure, including pressure on the whole heart, and, consequently, to an improvement of right ventricular overload and left ventricular diastolic dysfunction. In effect, it has been shown that indacaterol significantly reduces lung hyperinflation in acute conditions [41]. This reduction is associated with a significant increase of the right ventricular compliance indexes and may have a role in improving left ventricular preload leading to a reduction in cardiac frequency.
Ultra-LABAs and combination therapies
Three fixed-dose combination formulations (FDCs) containing an ultra-LABA and a LAMA have been developed indacaterol/glycopyrronium [15], vilanterol/ umeclidinium [20], and olodaterol/tiotropium [18]. Addition of an ultra-LABA to a LAMA not only induces a larger bronchodilation than that obtained with the LAMA as monotherapy, but also significantly improves many patient reported outcomes. In fact, a systematic review with meta-analysis that incorporated the data from trials lasting at least 3 months [12] has shown that these three ultra-LABA/LAMA combinations are always more effective than the LAMA or ultra-LABA alone in terms of the improvement not only in trough FEV1, but also in transitional dyspnoea index and St. George' s Respiratory Questionnaire scores.
This finding is nor surprising because there is recent preclinical documentation that combining an ultra-LABA with a LAMAat lower concentrations than those used in therapy provides a pharmacological synergistic benefit on airway smooth muscle relaxation [8], which may have major implications for the use of ultra-LABA/
LAMA FDCs in the treatment COPD [11]. Unfortunately, the synergistic effect is difficult to be documented in patientssuffering from COPD, although it can be shown after acute administration of the two bronchodilators [9], mainly because the choice of the doses to be used in the clinical development of ultra-LABA/LAMA FDCs has always been done without having previously performed studies to determine the optimal concentrations able to induce synergism in human isolated airways and we strongly believe that this is a mistake because, as already mentioned in the past "the doses extrapolated from ex vivo studies may provide a translational approach to design clinical trials that would promptly offer information on the optimal doses of LAMA/LABA combination inducing synergistic bronchodilation in COPD patients" [12].
In any case, the results of the already mentioned meta-analysis [12] have documented that the twice-daily indacaterol/glycopyrrolate 27.5/15.6 ^g FDC (glycopyrrolate 15.6 ^g, excluding the bromide salt, is equivalent to 12.5 ^g glycopyrronium), which hasbeen developed in the United States, is as effective as the -daily indacaterol/glycopyrronium 110/50 ^g FDC, a finding that fully supports our opinion.
The innovative information generated by the use of ultra-LABA/LAMA FDCs is that at least indacaterol/ glycopyrronium FDC seems to be more effective than salmeterol/fluticasone FDC in preventing COPD exacerbations in patients with a history of exacerbation during the previous year [42]. It is well known that non-neuronal acetylcholine (ACh) has inflammatory properties and the multitude of cells in the airways, including bronchial epithelial cells, neutrophils, lymphocytes, macrophages and fibroblasts, involved in exacerbations of COPD, have muscarinic receptors [43]. There is evidence that co-administration of indacaterol and glycopyrronium reduces the release of nonneuronal ACh, ACh that is released from the epithelium but not from bronchi [8].
The important role of combination therapy with an ICS and a LABA in the treatment of severe COPD patients with frequent exacerbations [22]reveals major marketing chances. Consequently, the pharmaceutical industry has a real interest in also developing anultra-LABA/once daily ICSFDC, in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy, and likely also to overcome the loss of patent protection [4].
At present time, vilanterol/fluticasone furoate is the only ultra-LABA/once daily ICS FDC approved for the long-term, once daily, maintenancetreatment of airflow obstruction in COPD patients,including chronic bronchitis and/or emphysema and toreduce exacerbations of COPD in patients with a history ofexacerbations [19].
The growing body of evidence suggests that triple therapy with LABAs, LAMAs, and ICS is efficacious making it an attractive combination in COPD. Therefore, a variety of triple combinations are currently under development [44]. However, the vilanterol/umeclidinium/ fluticasone furoate combination is the only triple therapy under development that includes an ultra-LABA.Two recent randomized studies evaluated the efficacy and
safety of umeclidinium added to vilanterol/fluticasone furoate in patients with moderate-to-very-severe COPD. The results of these studies documented that the addition of umeclidinium to vilanterol/fluticasone furoate resulted in significant improvements in lung function compared with vilanterol/fluticasone furoate, with similar safety profiles, though the impact on quality of life was inconsistent [45].The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of this triple combination versus vilanterol/fluticasone furoate or vilanterol/umeclidinium over a 52-week treatment period [46]. The study aims to recruit 10000 symptomatic advanced COPD patients (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) with an exacerbation in the previous 12 months.The anticipated completion date is July 2017.
It is likely that also a fixed dose combination with indacaterol/glycopyrronium/mometasone will be developed on a once-daily basis. However, there is still no available information although apparently it is under development only in patients with asthma.
Novel ultra-LABAsstill
under clinical development
Abediterol (AZD0548) is a new ultra-LABA that in preclinical setting showed superior bronchodilatory potency and similar or superior selectivity for p2-adrenoreceptors over p1-adrenoreceptors but a reduced effect on heart rate compared with formoterol, indacaterol, salmeterol, vilanterol and olodaterol [47, 48].Furthermore, this new ultra-LABAexhibited a long residence time at the human p2-adrenoceptor, with a much slower dissociation half-life than indacaterol, olodaterol and vilanterol [49].
A Phase II, randomized study has documented that abediterol 0.625-2.5 ^g provided dose-dependent, clinically and statistically significant bronchodilation versus placebo in 62 patients with mild-to-moderate asthma who were also receiving an ICS, with a peak effect similar to salbutamol and duration of action compatible with once daily dosing [50]. All doses of abediterol were well tolerated. Also in 70 COPD patients who were GOLD stage 2/3, all doses of abediterol (0.625-10 ^g) provided clinically and statistically significant, dose-dependent improvements in bronchodilation versus placebo, and were well tolerated [51]. Interestingly abediterol 2.5, 5 and 10 ^g gave significant improvements versus indacaterol.
PF-610355 is a member of a series of potent and selective sulfonamide derived p2-adrenoceptor agonists [52]. In healthy subjects, duration of action of PF-610355 450 ^g on airways determined by plethysmography was superior to salmeterol 50 ^g by 9.77 h indicating the potential for sustained pharmacological effect in the lung [53]. A preliminary trial documented that PF-610355 induced a clear 24 h bronchodilator effect in asthmatic patients [54].In patients with COPD, it has been estimated that once daily fine-particle dose of 28.1 ^g versus placebo has a moderate probability of providing an average improvement above 100 mL at trough [55]. The 50 ^g fine-particle dose, on the other hand, has a greater than 0.78 probability of achieving a 120 mL improvement versus placebo at trough.A pharmacokinetic/pharmacodynamic analysis suggested
that no relevant effects of PF-610355 on heart rate in COPD patients should be expected for doses up to 280 |jg once daily [56]. Although this interesting profile, in 2011 the development of the compound for the treatment of asthma and COPD was discontinuedlikely for strategic and regulatory reasons. We are confident that the interesting pharmacological and clinical profile of PF-610355 will induce the further development of this ultra-LABA.
AZD3199 is another novel inhaled, selective ultra-LABA. It has been selected froma new series of dibasic C-1 des-hydroxy 7-hydroxy benzthiazolone p2-adrenoreceptor agonists and is highly selective (>1500-fold) for the human p2-adrenoreceptors (pEC50 7.9 ± 0.12 (n = 8)) over human pr and p3-adrenoreceptors s [57].AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life [58]. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients with COPD. In asthmatic patients, AZD3199 480 ^g and 1920 ^g produced 24-hour bronchodilation [59]. At comparable peak bronchodilator effect, AZD3199 was associated with a lower level of systemic side effects than formoterol. In COPDthree different doses of AZD3199 (200, 400 or 800 jg o.d.) produced effective bronchodilation with 24-hour duration of action that was comparable to, or greater than, that achieved with formoterol twice daily [60]. However, no clear dose-response was observed for the bronchodilatory effects of AZD3199 at either peak or trough effects
A network meta-analysis that included >200 randomised trials showed that AZD3199 was the most effective agent in having a reduced risk of mortality in COPD patients (OR 0.45, 95%CI 0.02-10.32) [61].
Milveterol is being developed as an ultra-LABA for use in patients with asthma and COPD. Preclinical studies demonstrated high potency in vitro and long duration of action in a guinea pig model of bronchoprotection [62].The currently available information about its clinic efficacy is scarce and has not been presented or published yet.
Ultra-LABAs in preclinical development
The optimisation of two series of 4-hydroxybenzo-thiazolone derived p2-agonists, bearing a-substituted cy-clopentyl and p-phenethyl amino-substituentshas led to identification of the a-substituted cyclopentyl analogue 2 as the optimal compound [63]. It combines a rapid onset of action, with a comparable intrinsic duration of action to indacaterol, and has a favourable tolerability profile with respect to the systemic p2-adrenoceptor mediated side effects that are associated with the targeted levels of bronchodilation.
Sulfone 10b was identifiedfrom series of novel, potent, and selective human p2-agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol [64]. Although it showed a salmeterol-like potency and selectivity profile, it had longer duration of action than salmeterol in guinea pig in vivo, suitable for once daily dosing. Furthermore, it displayed lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes with metabolites that would be
expected to have reduced or no p2 activity. Being free of any genetic toxicity issues, it was considered as a backup to vilanterol.
TD-5471, a potent and selective full agonist of the human p2- adrenoceptor, was identified as the most promising agent of a series of potent p2-agonists incorporating a biarylamine secondary binding group [65].
Amines are known to have a high affinity for lung tissue (possibly through lysosomal partitioning) and their addition to the neutral secondary binding group of an existing p2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites [66]. The introduction of basic secondary binding groups to the salmeterol scaffold and blocking the site of metabolism to prevent aldehyde formation generated TD-4306, a p2-agonist with superior duration of action relative to salmeterol. In the guinea pig model of in vivo bronchoprotection, bronchoprotection at 72 h was dose-dependent and was significantly greater than salmeterol at nebulizer concentrations of >30 ^g/m.
Expert Commentary
The huge interest in developing new ultra-LABAs in the last decade has apparently declined progressively in recent times. Although, as already mentioned,indacaterol is cost-effective compared to tiotropium and salmeterol [33] and notwithstanding what we have previously illustrated on the potential positioning of ultra-LABAs in the treatment of COPD, no guideline indicates ultra-LABAs as first choice drugs compared to LAMAs. In effect, there is not published evidence that ultra-LABAs are definitely more effective than LAMAs as monotherapy. In particular, in the INVIGORATE study tiotropium produced a small (absolute difference 11 ml) and likely not of clinical significance, but statistically greater, improvement in trough FEV1 than indacaterol. Even though indacaterol reduced the rescue medication use, numerically fewer exacerbations occurred among the participants taking tiotropium [67].
On the other hand, in general even the prescribing behaviour of specialists does not seem to favour the use of LABAs as monotherapy in the treatment of COPD. The Adelphi Respiratory Disease Specific Programme, a cross-sectional survey of consulting patients in five European countries and in the US, showed a conflict between the current real-world practice and the GOLD 2011 updated treatment recommendations, documenting that even large proportions of patients in the low risk groups were currently receiving ICS/ LABA, either alone or in combination with a LAMA [68]. Furthermore, LABAs as monotherapy were only prescribed in a small percentage of patients in GOLD group A and B.
The documentation that in real life, the switch from LAMA to LABA and also the step downs of ICS/LABA to LABA or LAMA are infrequent [69] is interesting to understand the progressive decline in interest in developing new ultra-LABAs as monotherapy.
In any case, it is possible that the safety warning released by the U.S. Food and Drug Administration (FDA) in 2010 for the use of inhaled LABAs [70] has reduced the interest in this class of bronchodilators
and, actually, vilanterol has not been introduced into the market as a single agent.On the other hand, an emphasized contraindication to LABA monotherapy without another controller medicationat least in asthma [70] and the documented best pharmacological effect that is achieved by combining a LABA with a LAMA [11] with a larger bronchodilation and a better improvement in patient-reported outcomes and a better improvement in some patient-reported outcomes in patients with COPD [12] are strong arguments against the use the ultra-LABAs as monotherapy. This contrasts with the evidence that at least in US new LABA starts have been significantly reduced over time among those with a diagnosis of asthma, but they are largely unchanged in those without such a diagnosis [71].
Nevertheless, ultra-LABAs remain extremely useful drugs because they guarantee a greater adherence to the treatment as a result of the simplification of treatment with the reduction of the daily dose to be taken [72]. Nonadherence to prescribed medications is one of the major obstacles to successful management of COPD [73], but, inexcusably, adherence to COPD prescribed therapy is generally very poor [74]. Furthermore, ultra-LABAs also allow the combination with other classes of drugs, such as LAMAs and ICSs, that are fundamental for treating COPD and now are administered on a once daily basis [4]. In fact, as already mentioned, the treatment of COPD is generally based on the assumption of drug combinations (LABA/LAMA and ICS/LABA) in which p2-agonists are commonly included.
Five-year view
It is likely that over the next 5 years there will be less and less interest in the use of ultra-LABAs as monotherapy in COPD. The apparent lack of commercial success of indacaterol, the fact that olodaterol has only a single dose irrespective of COPD severity and the evidence that vilanterol will not be used as monotherapy provide a strong presumption that physicians will move always more their attention to LAMAs if they will prefer to prescribe a long-acting bronchodilator as monotherapy. Alternatively, we can suppose the possibility of starting the treatment of COPD patients administering low doses of LABA/LAMA combinations in order to optimize the bronchodilation [75]. This alternative approach would provide a patient-tailored therapy, with the further relevant advantage of reducing the risk of potential adverse events that characterize both LABAs and LAMAs, especially when inhaled at the full doses currently approved for the treatment of COPD [11].
This will mean that we should have available different doses of LABA/LAMA FDCs, a nonirrational eventuality considering that, as already mentioned, the twice-daily indacaterol/glycopyrrolate 27.5/15.6 ^g seems to be as effective the once daily indacaterol/ glycopyrronium110/50 ^g FDC [12].
Transparency. The study did not have sponsorship. The authors are fully responsible for the submission of the final version of the manuscript.
Financial and other relationships declaration. All authors participated in concept and design of the article and manuscript writing. The final version of the manuscript was approved by all authors. Authors did not receive fees for research.
REFERENCES
1. Cazzola M, Matera MG, Lötvall J. Ultra long-acting ß2-agonists in development for asthma and chronic obstructive pulmonary disease.Expert Opin Investig Drugs. 2005; 14: 775-783.
2. Matera MG, Cazzola M. Ultra-long-acting ß2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? Drugs. 2007; 67: 503-515.
3. Cazzola M, Matera MG. Emerging inhaled bronchodilators: an update. Eur Respir J. 2009; 34: 757-769.
4. Cazzola M, Calzetta L, Matera MG. B2-adrenoceptor agonists: current and future direction. Br J Pharmacol. 2011; 163: 4-17.
5. Cazzola M, Rogliani P, Segreti A et al. An update on bronchodilators in Phase I and II clinical trials. Expert Opin Investig Drugs. 2012; 21: 1489-1501.
6. Cazzola M, Page CP, Rogliani P et al. ß2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187:690-696.
7. Cazzola M, Calzetta L, Page CP et al. Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi. Eur J Pharmacol.2014;745:135-143.
8. Cazzola M, Calzetta L, Puxeddu E et al. Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells. Respir Res. 2016; 17: 70.
9. Cazzola M, Calzetta L, Segreti A et al. Translational study searching for synergy between glycopyrronium and indacaterol. COPD. 2015; 12: 175-181.
10. Cazzola M, Calzetta L, Ora J et al.Searching for the synergistic effect between aclidinium and formoterol: From bench to bedside. Respir Med. 2015; 109: 1305-1311.
11. Calzetta L, Matera MG, Cazzola M. Pharmacological interaction between LABAs and LAMAs in the airways: optimizing synergy. Eur J Pharmacol. 2015; 761: 168-173.
12. Calzetta L, Rogliani P, Matera MG et al. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest. 2016; 149: 1181-1196.
13. Cazzola M, Calzetta L, Page CP et al. Use of indacaterol for the treatment of COPD: a pharmacokinetic evaluation. Expert Opin Drug Metab Toxicol. 2014; 10: 129-137.
14. Matera MG, Rogliani P, Cazzola M. Indacaterol for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother .2015; 16: 107-115.
15. Matera MG, Rogliani P, Cazzola M. QVA149 (indacaterol/ glycopyrronium) for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2015; 16: 1079-1090
16. Matera MG, Ora J, Cazzola M. Differential pharmacology and clinical utility of long-acting bronchodilators in COPD — focus on olodaterol. Ther Clin Risk Manag. 2015; 11: 1805-1811
17. Cazzola M, Rogliani P, Ora J et al. Olodaterol + tiotropium bromide for the treatment of chronic obstructive pulmonary disease. Expert Rev Clin Pharmacol. 2015; 8: 529-539.
18. Calzetta L, Ciaprini C, Puxeddu E et al. Olodaterol + tiotropium bromide for the treatment of COPD. Expert Rev Respir Med. 2016; 10: 379-386.
19. Matera MG, Capuano A, Cazzola M. Fluticasone furoate and vilanterol inhalation powder for the treatment of COPD. Expert Rev Respir Med. 2015; 9: 5-12.
20. Matera MG, Rogliani P, Rinaldi B et al. Umeclidinium bromide + vilanterol (ANORO) for the treatment of chronic obstructive pulmonary disease. Expert Rev Clin Pharmacol. 2015; 8: 35-41.
21. Calzetta L, Rinaldi B, Cazzola M et al. Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate +
vilanterol for the treatment of asthma. Expert Opin Drug Metab Toxicol. 2016; 12: 813-822.
22. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (updated 2016). Available from: http://www.goldcopd.org/ uploads/users/files/GOLD_Report%202016.pdf.
23. Kerstjens HA, Deslée G, Dahl R et al. The impact of treatment with indacaterol in patients with COPD: A post-hoc analysis according to GOLD 2011 categories A to D. Pulm Pharmacol Ther. 2015; 32: 101-108.
24. Mahler DA, Kerstjens HA, Donohue JF et al. Indacaterol vs tiotropium in COPD patients classified as GOLD A and B. Respir Med. 2015; 109: 1031-1309.
25. Ferguson G, Sachs P, Hamilton A et al. Efficacy of olodaterol once daily (QD) via Respimat in GOLD 2/3 COPD patients not receiving background therapy: pooled data from 48-week studies [abstract]. Chest. 2013; 144 (4_meetingabstracts): 727A.
26. Mahler DA, Buhl R, Lawrence D et al. Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity. Pulm Pharmacol Ther. 2013; 26: 348-355.
27. Rossi A, van der Molen T, del Olmo R et al. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/ fluticasone in moderate COPD. Eur Respir J. 2014; 44: 1548-1556.
28. Singh MP. Indacaterol therapy in moderate-to-severe chronic obstructive pulmonary disease: findings from a single-center primary care cohort. Int J Chron Obstruct Pulmon Dis. 2013; 8: 613-619.
29. Wedzicha JA, Buhl R, Lawrence D et al. Monotherapy with indacaterol once daily reduces the rate of exacerbations in patients with moderate-to-severe COPD: Post-hoc pooled analysis of 6 months data from three large phase III trials. Respir Med. 2015; 109: 105-111.
Decramer ML, Chapman KR, Dahl R et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med. 2013; 1: 524-533.
Pascoe S, Locantore N, Dransfield MT et al. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015; 3: 435-442. Iqbal A, Barnes NC, Brooks J. Is blood eosinophil count a predictor of response to bronchodilators in chronic obstructive pulmonary disease? Results from post hoc subgroup analyses. Clin Drug Investig. 2015; 35: 685-688. Price D, Asukai Y, Ananthapavan J et al. A UK-based cost-utility analysis of indacaterol, aonce-daily maintenance bronchodilator for patients with COPD, using real world evidence on resource use. Appl Health Econ Health Policy. 2013; 11: 259-274.
34. Cazzola M, Page CP, Calzetta L et al. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev. 2012; 64: 450-504.
35. Cazzola M, Matera MG, Donner CF. Inhaled ß2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs. 2005; 65: 1595-1610.
36. Xia N, Wang H, Nie X. Inhaled long-acting ß2-agonists do not increase fatal cardiovascular adverse events in COPD: A meta-analysis. PLoS One. 2015; 10: e0137904.
37. McGarvey L, Niewoehner D, Magder S et al. One-year safety of olodaterol once daily via Respimat® in patients with GOLD 2-4 chronic obstructive pulmonary disease: results of a pre-specified pooled analysis. COPD. 2015; 12: 484-493.
30
31
32
33
40
41
38. Rinaldi B, Donniacuo M, Sodano L et al. Effects of chronic treatment with the new ultra-long-acting ß2-adrenoceptor agonist indacaterol alone or in combination with the ß1-adrenoceptor blocker metoprolol on cardiac remodelling. Br J Pharmacol. 2015; 172: 3627-3637.
39. Matera MG, Calzetta L, Cazzola M. ß-Adrenoceptor modulation in chronic obstructive pulmonary disease: present and future perspectives. Drugs. 2013; 73: 16531663.
Segreti A, Fiori E, Calzetta L et al. The effect of indacaterol during an acute exacerbation of COPD. Pulm Pharmacol Ther. 2013; 26: 630-634.
Santus P, Radovanovic D, Di Marco S et al. Effect of indacaterol on lung deflation improves cardiac performance in hyperinflated COPD patients: an interventional, randomized, double-blind clinical trial. Int J Chron Obstruct Pulmon Dis. 2015; 10: 1917-1923.
42. Wedzicha JA, Banerji D, Chapman KR et al. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016; 374: 2222-2234.
43. Wessler I, Kirkpatrick CJ.Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol. 2008; 154: 1558-1571.
44. Cazzola M, Matera MG. Triple combinations in chronic obstructive pulmonary disease — is three better than two? Expert Opin Pharmacother. 2014; 15: 2475-2478.
45. Siler TM, Kerwin E, Sousa AR et al. Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: Results of two randomized studies. Respir Med. 2015; 109: 1155-1163.
46. Pascoe SJ, Lipson DA, Locantore N et al. A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol. Eur Respir J. 2016; 48: 320-330.
47. Aparici M, Gomez-Angelats M, Vilella D et al. Pharmacological characterization of abediterol, a novel inhaled ß2-adrenoceptor agonist with long duration of action and a favorable safety profile in preclinical models. J Pharmacol Exp Ther. 2012; 342: 497-509.
48. Aparici M, Gavaldà A, Ramos I et al. In vitro and in vivo preclinical profile of abediterol (LAS100977), an inhaled long-acting ß2-adrenoceptor agonist, compared with indacaterol, olodaterol and vilanterol. Eur J Pharmacol. 2016; 770: 61-69.
49. Miralpeix M, Letosa M, Aparici M et al. Abediterol, a novel long-acting ß2 agonist, has a fast association rate and long residence time at human ß2 receptors [abstract]. Eur Respir J. 2014; 44: P3328.
50. Singh D, Pujol H, Ribera A et al. A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting ß2-adrenergic agonist, in asthma; a Phase II, randomized study. BMC Pulm Med. 2014; 14: 176.
51. Beier J, Pujol H, Seoane B et al. Abediterol, a novel long-acting ß2-agonist: bronchodilation, safety, tolerability and pharmacokinetic results from a single-dose, dose-ranging, active-comparator study in patients with COPD. BMC Pulm Med. 2016; 16: 102.
52. Glossop PA, Lane CAL, Price DA et al. Inhalation by design: novel ultra-long-acting ß2-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup. J Med Chem. 2010; 53: 6640-6652.
53. Li GL, Maclnyre F, Surujbally B et al. Pharmacokinetics of PF-00610355, a novel inhaled long-acting ß2-adrenoceptor agonist[abstract]. Eur Respir J. 2009; 34: 777s-778s.
54. Ward J, Macintyre F, Jones I et al. Randomised doubleblind, study to determine the efficacy and safety of a once-daily inhaled ß2-adrenoceptor agonist, PF-00610355 in asthmatic patients [abstract]. Eur Respir J. 2009; 34: 778s-780s.
55. Nielsen JC, Hutmacher MM, Cleton A et al. Longitudinal FEV1 dose-response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease. J Pharmacokinet Pharmacodyn. 2012; 39: 619634.
56. Diderichsen PM, Cox E, Martin SW et al. Predicted heart rate effect of inhaled PF-00610355, a long acting ß-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol. 2013; 76: 752-762.
57. Stocks MJ, Alcaraz L, Bailey A et al. Discovery of AZD3199, An inhaled ultralong acting ß2 receptor agonist with rapid onset of action. ACS Med Chem Lett. 2014; 5: 416-21.
58. Bjermer L, Kuna P, Jorup C et al. Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting ß2-adrenoreceptor agonist (uLABA). Drug Des Devel Ther. 2015; 9: 753-762.
59. Bjermer L, Rosenborg J, Bengtsson T et al. Comparison of the bronchodilator and systemic effects of AZD3199, an inhaled ultra-long-acting ß2-adrenoceptor agonist, with formoterol in patients with asthma. Ther Adv Respir Dis. 2013; 7: 264-271.
60. Kuna P, Ivanov Y, Trofimov VI et al. Efficacy and safety of AZD3199 vs formoterol in COPD: a randomized, doubleblind study. Respir Res. 2013; 14: 64.
61. Tricco AC, Strifler L, Veroniki AA et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open. 2015; 5: e009183.
62. Jacobsen JR, Choi SK, Combs J et al. A multivalent approach to the discovery of long-acting ß2-adrenoceptor agonists for the treatment of asthma and COPD. Bioorg Med Chem Lett. 2012; 22: 1213-1218.
63. Arnold N, Beattie D, Bradley M et al. The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting ß2-adrenoceptor agonist. Bioorg Med Chem Lett. 2014; 24: 4341-4347.
64. Procopiou PA, Barrett VJ, Biggadike K et al. Discovery of a rapidly metabolized, long-acting ß2 adrenergic receptor
agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing. J Med Chem. 2014; 57: 159-170.
65. Jacobsen JR, Aggen JB, Church TJ et al. Multivalent design of long-acting ß2-adrenoceptor agonists incorporating biarylamines. Bioo rg Med Chem Lett. 2014; 24: 2625-2630.
66. McKinnell RM, Klein U, Linsell MS et al. Discovery of TD-4306, a long-acting ß2-agonist for the treatment of asthma and COPD. Bioorg Med Chem Lett. 2014; 24: 2871-2876.
67. Decramer ML, Chapman KR, Dahl R et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med. 2013; 1: 524-533.
68. Vestbo J, Vogelmeier C, Small M et al. Understanding the GOLD 2011 Strategy as applied to a real-world COPD population. Respir Med. 2014; 108: 729-736.
69. Wurst KE, Punekar YS, Shukla A. Treatment evolution after COPD diagnosis in the UK primary care setting. PLoS One. 2014; 9: e105296.
70. Chowdhury BA, Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med. 2010; 362: 1169-1171.
71. Hartung DM, Middleton L, Markwardt S et al. Changes in long-acting ß-agonist utilization after the FDA's 2010 drug safety communication. Clin Ther. 2015; 37: 114-123.
72. Toy EL, Baulieu NU, McHale JL et al. Treatment of COPD: relationship between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011; 105 (3): 435-441.
73. Vestbo J, Anderson JA, Calverley PM et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009; 64: 939-943
74. Âgh T, Inotai A, Mészaros À. Factors associated with medication adherence in patients with chronic obstructive pulmonary disease. Respiration 2011; 82: 328-334.
75. Cazzola M, Rogliani P, Matera MG. Escalation and de-escalation of therapy in COPD: myths, realities and perspectives. Drugs. 2015; 75: 1575-1585.
© А.А. Визель, И.Ю. Визель, Н.Б. Амиров, 2017
УДК 616.24-004(048.8) DOI: 10.20969/VSKM.2017.10(1).14-21
ИДИОПАТИЧЕСКИЙ ЛЕГОЧНЫЙ ФИБРОЗ: СОСТОЯНИЕ ПРОБЛЕМЫ
ВИЗЕЛЬ АЛЕКСАНДР АНДРЕЕВИЧ, докт. мед. наук, профессор, зав. кафедрой фтизиопульмонологии ФГБОУ ВО «Казанский государственный медицинский университет» Минздрава России, главный внештатный специалист-пульмонолог Минздрава Татарстана, Россия, 420012, Казань, ул. Бутлерова, 49, e-mail: lordara@inbox.ru ВИЗЕЛЬ ИРИНА ЮРЬЕВНА, канд. мед. наук, профессор РАЕ, ассистент кафедры фтизиопульмонологии ФГБОУ ВО «Казанский государственный медицинский университет» Минздрава России, Россия, 420012, Казань, ул. Бутлерова, 49, e-mail: tatpulmo@mail.ru
АМИРОВ НАИЛЬ БАГАУВИЧ, докт. мед. наук, академик РАЕ, профессор кафедры общей врачебной практики ФГБОУ ВО «Казанский государственный медицинский университет» Минздрава России, Россия, 420012, Казань, ул. Бутлерова, 49, e-mail: namirov@mail.ru
Реферат. Цель исследования — провести анализ публикаций и подготовить обзор работ, посвященных современному пониманию идиопатического легочного фиброза и его лечению. Материал и методы. Изучены публикации отечественных и зарубежных авторов. Результаты и их обсуждение. Идиопатический легочный фиброз является особой формой хронической прогрессирующей фиброзирующей интерстициальной пневмонии неизвестной этиологии, которая возникает преимущественно у людей старшего возраста, поражает только легкие и связана с гистологическим и/или рентгенологическим паттерном обычной интерстициальной пневмонии. Прогноз течения идиопатического легочного фиброза хуже, чем у ряда онкологических заболеваний. Диагностика идиопатического легочного фиброза основана на результате мультидисциплинарного заключения пульмонолога, рентгенолога и морфолога. Ведущим диагностическим критерием является совокупность данных рентгеновской компьютерной томографии высокого разрешения: преобладание изменений в базальных, кортикальных отделах легких; диффузные ретикулярные изменения; сотовое легкое с тракционными бронхоэктазами и без них; отсутствие любых признаков, противоречащих данной патологии. Функциональная оценка состояния больных основана на измерении жизненной емкости легких и диффузионной способности. Хирургические методы получения образцов тканей рекомендуются только при несоответствии лучевых признаков идиопатического легочного
