Clinicopharmacological profile of the fixed-dose combination of aclidinium bromide and formoterol fumarate in the management of chronic obstructive pulmonary disease

Long-acting β₂ agonists in COPD

Forced expiratory volume in 1 second (FEV1) has served as an important tool to categorize disease severity and to grade the effectiveness of treatment regimens. The control of symptoms using bronchodilators is the mainstay of treatment. Based on the assessment of the GOLD guidelines, the recommended choice of therapy for Group A patients are short-acting agents. Patients in or above Group B require a long-acting bronchodilator; this would involve either a long-acting β₂ agonist (LABA) or a long-acting anticholinergic (LAMA).

Formoterol and salmeterol are LABAs that are effective in the treatment of COPD. Differences in their pharmacology exists with formoterol being a full β₂ receptor agonist whilst salmeterol a partial agonist. Formoterol furthermore has a rapid onset of action compared with salmeterol. Seberova and Andersson showed that the onset of bronchodilatory effect, as measured by serial FEV1, for formoterol and salbutamol are similar in asthmatics [Seberova and Andersson, 2000]. This study proves that formoterol, though considered to be a LABA, has a faster onset of action similar to the short-acting bronchodilator salbutamol. This difference was thought to be due to differences in their physicochemical properties. Formoterol is water soluble with some lipophilicity that ensures rapid bronchodilation followed by a prolonged effect. On the other hand, salmeterol may diffuse slowly to the β₂ receptors located on smooth muscle tissue thus explaining its slower onset of action [Rossi et al. 2008]. Several once-daily LABAs such as olodaterol, vilanterol and abideterol have either been recently approved or are in the late stages of clinical development. These agents are essentially full agonists at β₂ receptors and produce dose-dependent rapid bronchodilation that is maintained for more than 24 h [Malerba et al. 2012; Babu and Morjaria, 2014].

Whilst the use of LABAs does not have any effect on the progression of COPD as measured by a rate of decline in FEV1, LABAs do improve lung function [Cope et al. 2013], reduce the rate of exacerbation, improve both health-related quality of life [Man et al. 2003; Sin et al. 2003] and small airway patency with a consequent reduction in forced residual capacity (FRC), and increase inspiratory capacity (IC) [Di Marco et al. 2003; O’Donnell et al. 2004].

LAMAs and aclidinium bromide

The parasympathetic network of the airway wall regulates bronchoconstriction and mucus secretion through muscarinic receptors. There are five different types of muscarinic receptors (M_1–5), although only M₁, M₂ and M₃ are expressed in human lungs. M₁ receptors facilitate neurotransmission. M₂ receptors are expressed on both presynaptic and parasympathetic nerve endings at the neuromuscular junction and on bronchial smooth muscles, thus are involved in either inhibiting or promoting bronchoconstriction depending on their site of stimulation. M₃ receptors control bronchomotor tone and mucus secretion and are expressed on bronchial smooth muscle, submucosal glands and vascular endothelium [Sims and Panettieri, 2011], and are therefore the primary target for LAMAs.

Aclidinium bromide [(3R)-3-y-1-(3-phenoxypropyl)-1-azoniabicyclo (2,2,2) octane bromide] (Eklira™, Almirall SA/AstraZeneca, Spain) is a quaternary ammonium compound with a high binding affinity for the M₃ receptor. Aclidinium, along with glycopyrronium and tiotropium, binds to the M_1–5 receptors in a concentration-dependent manner with a greater selectivity for M₃ receptors than for M₂ [Prakash et al. 2013]. They also dissociate more slowly from the M₃ than they do from the M₂ receptors [Gavalda et al. 2009; Vogelmeier et al. 2011a]. The association rate of aclidinium with human M₃ receptors is 2.6 times faster than that of tiotropium, whilst glycopyrronium associates 4–5 times faster with M₃ receptors than tiotropium or aclidinium [Sykes et al. 2009; Ulrik, 2012]. The more rapid association of LAMA with the M₃ receptor is believed to underlie its faster onset of action. The dissociation half-life of aclidinium from the M₃ receptor is six times that of the M₂ receptor, which will therefore provide bronchodilation via M₃ receptors long after the less-desirable M₂ effects such as tachycardia diminish. The quaternary nature of the compound also imparts a low oral bioavailability and a low blood–brain barrier permeability.

During early phase I studies, aclidinium exhibited linear and time-dependent pharmacokinetics with a steady state achieved within a 7-day treatment period compared with tiotropium which required 2–3 weeks to reach a steady state [Reid and Carlson, 2014]. Aclidinium is rapidly converted into inactive alcohol and carboxylic acid with a plasma half-life of 2.2 min compared with more than 60 min for both ipratropium and tiotropium. Furthermore, the metabolites of aclidinium do not have any affinity for muscarinic receptors. As aclidinium undergoes rapid hydrolysis to its inactive metabolites in the plasma, very little is excreted within the urine and renal dysfunction does not appear to have an impact on systemic exposure [Schmid et al. 2010].

Rationale for dual bronchodilation

The dose–response curve for LABA and LAMA demonstrates a linear response at lower concentrations followed by a flatter curve at higher concentrations [Ball et al. 1991; Casarosa et al. 2009]. This indicates only a marginal improvement in benefit with a greater side effect profile when increasing the dose of these medications. Interestingly, this attribute is also shared by other inhaled medications. Formoterol is a LABA with a faster onset of action and a relatively linear dose–response curve [Cazzola et al. 2012a]. Physicians have been using the concept of dual bronchodilation with short-acting β₂ agonists and antimuscarinic agents in the form of a Combivent^® inhaler and nebulizer solutions. Studies combining LABAs and LAMAs using separate devices have demonstrated an additive effect but the benefit achieved has varied greatly between studies [Van Noord et al. 2006; Tashkin et al. 2008; Hanania et al. 2009]. Despite this, these studies do support the rationale of adding bronchodilators with different mechanisms of action.

When one considers the primary outcome variable of symptoms and health-related quality of life, LABAs are more effective than LAMAs, while LAMAs with a favourable impact on the above endpoints appear to be more effective in reducing exacerbations [Vogelmeier et al. 2011b; Rodrigo and Neffen, 2012; Cope et al. 2013]. Combining these bronchodilators can thus have a favourable response effect. The symptoms of COPD vary throughout the day with symptoms being at their worst in the mornings. Hence, a morning dose of formoterol with its faster onset of action can help with improving these symptoms [Roche et al. 2013]. Adherence to medication is a concern if the medication does not relieve symptoms promptly. The addition of formoterol as a LABA would therefore provide reassurance to the patient that the combination is acting effectively. Currently three LABA/LAMA combinations have been licensed: glycopyrronium bromide/indacaterol malaete (Ultibro^®, Novartis, Switzerland), umeclidinium bromide/vilantarol trifenatate (Anoro^®, GlaxoSmithKline, UK) and more recently aclidinium bromide/formoterol fumarate (Duaklir^®, Almirall SA/AstraZeneca, Spain). Another combination, tiotropium bromide/olodaterol (Boehringer Ingelheim, Germany) is currently undergoing phase III assessment.

Delivery devices

A number of inhalation devices are available for the delivery of medications to manage COPD. These include the pressurized metered dose inhalers (pMDIs) [Lavorini et al. 2011] and the increasingly popular breath-actuated dry powder inhalers (DPIs) [Nokhodchi and Larhrib, 2013]. Without a spacer device, pMDIs may pose a number of challenges for use compared with DPIs. These challenges include the lack of synchronized inhalation and actuation and attenuated oropharyngeal deposition in addition to drug delivery and potential resultant cost implications [Lavorini et al. 2008; Lavorini, 2013]. Despite numerous studies reporting excessive errors with the use of pMDIs, it has been suggested that this may also be the case with DPIs [Lavorini et al. 2008]. Critical errors in inhaler use may not only compromise treatment efficacy but may also compromise patient satisfaction, which is associated with improved inhaler concordance, resulting in improved clinical outcomes and reduced healthcare costs [Melani et al. 2011; Makela et al. 2013]. Thus, there is a need to develop easy-to-use inhalers that require minimal patient handling to ensure successful drug delivery which will ultimately enhance patient adherence and management of their underlying COPD.

Genuair^® (Almirall SA/Astra Zeneca, Spain) is a novel breath-actuated multidose DPI delivery inhaler that has been developed to achieve a reliable and effective delivery of inhaled licensed aclidinium and more recently aclidinium and formoterol (Duaklir™, Almirall SA/Astra Zeneca, Spain) for the management of COPD. The Genuair device, which resembles the Novolizer^® (MEDA Pharma GmbH, Germany), has a nonremovable powder cartridge and is a fully assembled ready to use inhaler that requires minimal patient handling and hence reduces the potential for error. The cyclone dispersion system and the Genuair mouthpiece deagglomerate the medication into small particles for a complete dose delivery within 2 l of inhalation as per recommendations [Chrystyn and Niederlaender, 2012]. There are two main steps for inhalation using the Genuair; pressing and releasing the blue button to activate the inhaler and inhaling strongly and deeply. The inhaler device has a number of feedback mechanisms for effective use including a control window that changes from red to green when the dose has been dispensed into the powder delivery channel and the dose is ready to be inhaled, an audible click sound when the patient inhales with the minimum inspiratory flow rate required, and following successful inhalation, the change of the window from green back to red [Magnussen et al. 2009; Newman et al. 2009; Chrystyn and Niederlaender, 2012]. For appropriate dosing, there is also a trigger threshold that prevents the release of a second dose into the powder delivery inhalation channel until complete inhalation has occurred in order to avoid double dosing. Importantly, on hearing the click the patient must continue to inspire, remove the inhaler from the mouth and hold their breath for as long as is comfortable before exhaling through their nose. The trigger flow rate is approximately 40 l/min; however, a constant fine particle fraction is achieved at flow rates above 35 l/min [Der Palen, 2014]. Moreover, the Genuair inhaler has a dose indicator with a warning line when only a few doses remain, in addition to having a lock-out mechanism which prevents use of the device after the final dose has been dispensed [Chrystyn and Niederlaender, 2012].

When choosing a new DPI for COPD patients, it is important to consider whether they can generate sufficient inspiratory flow in order to disaggregate the medication; the peak inspiratory flow (PIF) being inversely proportional to the intrinsic resistance of the device [Magnussen et al. 2009]. The PIF of the Genuair versus the Handihaler^® (Boehringher Ingelheim, Germany) device has been investigated in an open-labelled randomized crossover study using 48 patients with moderate to severe COPD [Magnussen et al. 2009]. The report indicated the mean PIF achieved for the Genuair to be significantly higher than that with the Handihaler, and 97.2% of inhalation through the Genuair to be successful and optimal. More recently an open-labelled randomized crossover study of 130 patients with moderate to severe COPD was conducted to assess patient preference and willingness to continue with either the Genuair or Handihaler fitted with a placebo [Van Der Palen et al. 2013]. Not only was there a significant overall (79.1% versus 20.9%, respectively) and individual domain preference for the Genuair device, but also patient satisfaction and willingness to continue using the Genuair was significantly higher based on the fact that markedly fewer patients had critical errors with its use (2.9% versus 19%, respectively) compared with the Handihaler. In a similar double-blind, placebo-controlled study of 414 patients, a comparable preferential and willingness to continue with the Genuair compared with the Handihaler was reported [Beier et al. 2013]. More recently, an in vitro study comparing four different inhaler devices [Genuair; Repsimat^®, Boehringher Ingelheim, Germany; Breezhaler, Novartis, Switzerland; and Handihaler], noted that the delivered dose was of the same order of magnitude for the former three devices (>89% of the label claim) but considerably lower for the Handihaler [Gjaltema et al. 2013].

Aclidinium bromide/formoterol fumarate (Duaklir^®)

The individual characteristics of both aclidinium and formoterol represent appropriate components for a fixed-dose combination (FDC), twice-daily LABA/LAMA; although preclinical data of the interaction between these two bronchodilators is limited. In this section we discuss a preclinical and phase I study, phase II studies and subsequently phase III studies that have eventually led to the licensing of this FDC.

Phase III studies

To date there have been two randomized, double-blind, placebo-controlled studies in various centres worldwide, evaluating the efficacy, safety and tolerability of two FDCs of aclidinium/formoterol (400/12 µg and 400/6 µg twice daily) versus aclidinium (400 µg) twice daily, formoterol (12 µg) twice daily and a placebo administered via the Genuair device over a 24-week period in moderate to severe stable COPD patients (AUGMENT (ITT, n = 1668) and ACLIFORM-COPD (ITT, n = 1726)) [D’Urzo et al. 2014a; Singh et al. 2014]. Both studies had the same primary outcome measures of morning predose (trough) FEV1 and morning 1h postdose FEV1 at week 24. The predefined coprimary endpoints in both the AUGMENT and ACLIFORM-COPD studies, reflect the Food and Drug Administration (FDA) guidelines regarding FDC drugs with each component of the FDC making a contribution to the claimed effects; that is a rapid onset bronchodilation with formoterol (change from baseline in FEV1 at 1 h post morning dose) [Benhamou et al. 2001; Tashkin and Ferguson, 2013] and 24 h bronchodilation with twice daily aclidinium (change from baseline in trough FEV1) [Jones et al. 2012; Kerwin et al. 2012]. In the AUGMENT study, both the FDCs (400/12 µg and 400/6 µg) showed significantly greater 1 h post-dose FEV1 compared with aclidinium monotherapy (108 and 87 ml, respectively, p < 0.0001) as well as trough FEV1 in patients treated with 400/12 µg FDC versus formoterol monotherapy (45 ml; p = 0.0102) and numerical improvement of 26 ml in favour of 400/6 µg FDC (p = 0.133) at 24 weeks [D’urzo et al. 2014a]. Similar significant improvements were noted in the ACLIFORM–COPD study at 24 weeks in 1 h post-dose FEV1 (400/12 µg and 400/6 µg versus aclidinium, 125 and 69 ml, respectively, p < 0.001 both) and trough FEV1 (400/12 µg and 400/6 µg versus formoterol, 85 and 53 ml, respectively, p < 0.01) [Singh et al. 2014]. Other secondary endpoints in both studies included the transitional dyspnoea index (TDI) focal score, a change from baseline in St George’s Respiratory Questionnaire (SGRQ), peak FEV1, FEV1 during 3 h post-dose, TDI and SGRQ responders [percentage of patients achieving the minimum clinically important difference (MCID) in TDI (⩾1 unit increase) and SGRQ (⩾4 units)]; changes from baseline in COPD symptoms [total exacerbations of chronic obstructive pulmonary disease tool (EXACT)–respiratory symptoms (E-RS) score and night time and early morning symptom scores]; rate of COPD exacerbations [healthcare resource utilisation (HCRU) and EXACT (only in ACLIFORM-COPD study)]; and change from baseline in relief medication use. These have been summarized in Tables 1–3.

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Table 1.

Changes in peak and 3 h FEV1 from baseline at day 1 and week 24 in the AUGMENT and ACLIFORM-COPD studies.

Parameter	Placebo	FDC 400/12 µg		FDC 400/6 µg		Aclidinium 400 µg		Formoterol 12 µg
			p value versus placebo		p value versus placebo		p value versus placebo		p value versus placebo
*Change from baseline in LSM Peak FEV1 day 1 (ml)
AUGMENT	–	216ΨΨΨ, ΩΩΩ	<0.001	208ΨΨΨ, ΩΩΩ	<0.001	- ¥	–	- ¥	–
ACLIFORM-COPD	–	- ¥	–	- ¥	–	- ¥	–	- ¥	–
*Change from baseline in LSM peak FEV1 week 24 (ml)
AUGMENT	–	285	<0.001	259	<0.001	- ¥	–	- ¥	–
ACLIFORM-COPD	–	299ΨΨΨ, ΩΩΩ	<0.001	253ΨΨΨ, ΩΩΩ	<0.001	178	<0.001	151	<0.001
*Change from baseline in LSM 3 h FEV1 day 1 (ml)
AUGMENT	–	258Ψ, Ω	<0.001	255Ψ, Ω	<0.001	165	<0.001	154	<0.001
ACLIFORM-COPD	–	-¥ ΨΨΨ, ΩΩΩ	<0.001	-¥, ΨΨ, ΩΩΩ	<0.001	- ¥	<0.001	- ¥	<0.001
*Change from baseline in LSM 3 h FEV1 week 24 (ml)
AUGMENT	–	298Ψ, Ω	<0.05	264Ψ, Ω	<0.001	174	<0.001	182	<0.001
ACLIFORM-COPD	–	-¥, ΨΨΨ, ΩΩΩ	<0.001	-¥, ΨΨΨ, ΩΩΩ	<0.001	- ¥	<0.001	- ¥	<0.001

FDC, fixed-dose combination; FEV1, forced expiratory volume in 1 second; LSM, least squares means

*

Change compared with placebo

-^¥Actual numerical data not available

Ψ

p < 0.05 FDC versus aclidinium; ^ΨΨ p < 0.01FDC versus aclidinium; ^ΨΨΨ p ⩽ 0.001FDC versus aclidinium.

Ω

p < 0.05 FDC versus formoterol; ^ΩΩ p < 0.01 FDC versus formoterol; ^ΩΩΩ p < 0.001 FDC versus formoterol.

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Table 2.

Changes in subjective parameters in the AUGMENT and ACLIFORM-COPD studies.

Parameter	Placebo	FDC 400/12 µg		FDC 400/6 µg		Aclidinium 400 µg		Formoterol 12 µg
			p value versus placebo		p value versus placebo		p value versus placebo		p value versus placebo
SM change in TDI focal scores at week 24 from baseline
AUGMENT	0.58	2.02 ΩΩ	<0.001	1.98	<0.001	1.56	⩽0.001	1.52	<0.01
ACLIFORM-COPD	1.22	2.51	<0.001	2.38	<0.001	2.11	<0.005	2.06	<0.005
% TDI responders at week 24†
AUGMENT	- ¥	- ¥	<0.001	- ¥	<0.001	- ¥	<0.01	- ¥	<0.01
ACLIFORM-COPD	45.5	64.8	<0.001	63.7	<0.001	56.5	<0.05	61.3	<0.01
LSM change in SGRQ at week 24 from baseline
AUGMENT	−2.21	−6.57	⩽0.001	−5.94	⩽0.001	−6.44	⩽0.001	−4.70	<0.05
ACLIFORM-COPD	−6.51	−7.16	NS	−8.34Ψ, ΩΩ	NS	−5.80	NS	−5.58	NS
% SGRQ responders at week 24 ≠
AUGMENT	38.7	58.2	⩽0.001	53.6	<0.05	54.5	⩽0.001	52.4	<0.05
ACLIFORM-COPD	53.2	55.3	NS	64.2	<0.05	- ¥	–	- ¥	–
Change overall mean daily E-RS scores at week 24 from baseline
AUGMENT	−0.94	−2.30	<0.05	−2.69Ψ, Ω	<0.05	−1.98	<0.05	−1.82	<0.05
ACLIFORM-COPD	−1.66	−2.48Ψ, Ω	<0.05	−2.82Ψ, Ω	<0.05	−1.59	<0.05	−1.79	<0.05
Change in early morning symptoms severity index mean daily scores at week 24 from baseline
AUGMENT	−0.11	−0.24 Ψ	<0.05	−0.26 Ψ	<0.05	−0.15	NS	−0.18	NS
ACLIFORM-COPD	−0.12	−0.21 ΨΨ	<0.05	−0.24ΨΨ, Ω	<0.05	−0.13	NS	−0.17	NS
Change in night-time symptoms severity index mean daily scores at week 24 from baseline
AUGMENT	−0.14	−0.26	<0.05	−0.29 Ψ	<0.05	−0.18	NS	−0.21	NS
ACLIFORM-COPD	−0.17	−0.24	NS	−0.29 ΩΩ	<0.01	−0.15	NS	−0.20	NS
*Change from baseline in overall mean daily reliever medication use
AUGMENT	–	−1.11 ΨΨ	<0.001	−1.10 ΨΨ	<0.001	−0.68	<0.001	−0.90	<0.001
ACLIFORM-COPD	–	−0.66 Ψ	<0.001	−0.73 Ψ	<0.001	- ¥	–	- ¥	–

E-RS, Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT) Respiratory Symptoms (11 items of the 14-item EXACT); FDC, fixed-dose combination; LSM, least squares means; NS, not significant; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnoea index.

-¥

Actual numerical not data available.

†

TDI responders defined as patients who had a minimal clinical important difference (MCID) ⩾1 unit improvement in TDI focal score at week 24 versus placebo.

≠

SGRQ responders defined as patients who had a minimal clinical important difference (MCID) ⩾4 units reduction in the SGRQ score at week 24 versus placebo.

Ψ

p < 0.05 FDC versus aclidinium; ^ΨΨ p < 0.01 FDC versus aclidinium.

Ω

p < 0.05 FDC versus formoterol; ^ΩΩ p < 0.01 FDC versus formoterol .

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Table 3.

Exacerbation frequency over 24 weeks in the ACLIFORM-COPD study.

Parameter	Placebo	FDC 400/12 µg		FDC 400/6 µg		Aclidinium (400 µg)		Formoterol (12 µg)
			p value		p value		p value		p value
Rate of COPD exacerbations* (any severity) /patient/year	0.36	0.26	–	0.29	–	0.29	–	0.41	–
% Reduction in rate of COPD exacerbations* (any severity) versus placebo	–	27 †	NS	20	NS	18	NS	-15	NS
% Reduction in rate of moderate to severe COPD exacerbations* versus placebo	–	23	NS	15	NS	- ¥		- ¥
EXACT criteria rate of events/patient /year	1.54	1.09	–	1.28	–	1.40	–	1.26	–
% Reduction EXACT criteria rate versus placebo	–	29 ≠	<0.05	17	NS	9	NS	18	NS

EXACT, Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT) (defined as a persistent increase from baseline in total EXACT score of ⩾9 points for ⩾3 days or ⩾12 points for ⩾2 days); FDC, fixed-dose combination.

*

Exacerbations defined as an increase of chronic obstructive pulmonary disease (COPD) symptoms during ⩾2 consecutive days that require a change in COPD treatment.

-¥

Actual numerical not data available.

†

p < 0.05 FDC 400/12 µg versus formoterol 12 µg.

≠

p < 0.05 FDC 400/12 µg versus aclidinium 400 µg.

More recently at an international conference, a 28 week extension study [ClinicalTrials.gov identifier: NCT01572792] of the 24-week AUGMENT study compared the FDC aclidinium/formoterol (400/12 µg), FDC aclidinium/formoterol (400/6 µg), aclidinium (400 µg), formoterol (12 µg) and a placebo administered twice daily in 1240 moderate to severe stable COPD patients [D’urzo et al. 2014b]. As with the primary study, the 28-week extension reported that treatment with FDC at 52 week resulted in significant and sustained improvements in lung function and dyspnoea compared with the placebo; with numerical improvements in favour of FDC aclidinium/formoterol 400/12 µg versus 400/6 µg. In a pooled analyses of the ACLIFORM-COPD and AUGMENT studies on the efficacy of FDC aclidinium/formoterol (400/12 µg) on exacerbations in moderate to severe COPD patients it was reported that the FDC attenuated the rate of moderate to severe COPD (29%) and EXACT (22%) exacerbations [Bateman et al. 2014].

Clinical perspectives

Current international recommendations propose the combined use of LABAs and LAMAs to maximize bronchodilation in COPD patients not controlled on a single bronchodilator [Global Initiative for Obstructive Lung Disease, 2013]. Prior to the invention of single-device dual bronchodilators, some patients were managed using single agents delivered in different inhalers, although this was uncommon, probably due to the inconvenience of handling two separate devices [Bourbeau and Bartlett, 2008; IMS Health LS, 2012]. The perspectives of physicians and payers regarding these newly licensed dual bronchodilators are awaited, although it would be a logical and appropriate choice for avoiding multiple drugs at high doses and hence attenuating adverse effects, improving concordance and maintaining simple treatment regimens for patients [National Institutes of Health, National Heart, Lung, and Blood Institute, 2012; Cazzola et al. 2013a]. Furthermore, it has been retrospectively reported that there may be pharmacoeconomic benefits of using a LAMA and LABA compared with monotherapy for managing stable COPD patients; in fact there was a suggestion that dual bronchodilator use was associated with lower healthcare-related costs compared with the use of triple therapy (LAMA, LABA and inhaled steroids) [Kozma et al. 2011]. These findings would advocate the rapid development of FDC dual bronchodilator therapy, especially on the basis of improved lung function and safety and tolerance in patients with moderate to severe COPD that has been observed with this class of therapy [Malerba et al. 2012; Prakash et al. 2015].

With the availability of once-daily and twice-daily LABAs and LAMAs, an important question is whether to choose a once-daily or a twice-daily administration of medication for patients with COPD. There is marked modulation of airway calibre over a 24-h period with short-acting bronchodilators. With extended duration of action, the 24-h profile of bronchial tone smoothens out leading to a net increase of AUC_0-24 for FEV1 (and additional lung function parameters such as forced vital capacity), and second to an increase of morning FEV1 after the last respective inhalation (trough FEV1) versus twice-daily and short-acting drugs [Beeh and Beier, 2010]. However, Wu and colleagues used a pharmacokinetic–pharmacodynamic model of longitudinal FEV1 response to an inhaled LAMA in COPD patients to show that with the same twice-daily regimen one can achieve a better trough FEV1, maximal response and AUC_0-24 [Wu et al. 2011]. There are no large-scale comparative studies that have looked at once-daily and twice-daily bronchodilators. However, a recent study showed that aclidinium provided improvements in early morning and night time symptoms that were greater than those observed with once-daily tiotropium [Beier et al. 2013]. Whilst the jury is out, twice-daily dosing should be considered a useful approach for COPD patients with nocturnal and early morning symptoms. The use of FDC circumvents an important problem of nonadherence to some medications. Though the adherence to a medication is multifactorial, tedious frequent dosing and the use of multiple inhalers do play an important role [Bourbeau and Bartlett, 2008]. Novel approaches such as bifunctional muscarinic β₂ agonists (MABAs) combine muscarinic antagonism and β₂ agonism in a single molecule [Cazzola et al. 2013b] which bypasses the potential problem of formulating different drugs in one inhaler and provides a simplified formulation and pharmacokinetics compared with individual combination therapy.