Dual LABA/LAMA bronchodilators in chronic obstructive pulmonary disease: why, when, and how

KEYWORDS:

• LABA
• LAMA
• combination
• synergy
• COPD

1. Introduction

Dual bronchodilation therapy is the cornerstone for the treatment of chronic obstructive pulmonary disease (COPD) [1]. Combining a long-acting β₂ adrenoceptor (β₂-AR) agonist (LABA) with a long-acting muscarinic antagonist (LAMA) in a fixed-dose combination (FDC) improves lung function, dyspnea, quality of life, and exercise tolerance and reduces the risk of exacerbations of COPD, thus leading to unquestionable clinical benefits compared with monocomponents [2–4].

The rationale for combining two bronchodilators with different mechanisms of actions should be (1) to induce synergism in therapeutic efficacy; (2) to reduce the overall risk of adverse events; and (3) to allow significant dose reductions for a given effect. Furthermore, the toxicities of the drugs should not overlap [5]. Combining two different drugs may lead to additive, synergistic, and antagonistic interaction. Overall, synergism is an effect that is more than additive, whereas antagonism is an effect that is less than additive. Thus, the main criterion for identifying synergism and/or antagonism is to quantify the additive effect. While the Bliss independence equation and unified theory are validated methods to identify the additive effect in vitro, only the Bliss independence approach represents a suitable method to be applied in clinical trials [6].

A large body of evidence demonstrates that LABA/LAMA combinations induce a strong synergistic bronchorelaxant effect in human isolated airways [7,8], and such a favorable interaction has been further confirmed in clinical trials [9,10]. Moreover, a recent post hoc analysis has demonstrated the clinical synergism between LABAs and LAMAs and that it not only induces a synergistic improvement in lung function, but also a synergistic improvement of dyspnea in COPD patients [11].

Nevertheless, recent findings suggested that the simple addition of a LABA to a LAMA in a FDC may be not sufficient to exceed the expected additive effect to induce synergistic interaction [1,12].

Therefore, considering that the mechanisms leading to the pharmacological interaction between LABAs and LAMAs have been at least partially elucidated [8,13,14], why, when, and how LABA/LAMA bronchodilators should be administered to patients with COPD are the key questions that remain to be clarified.

2. Rationale of combining a LABA with a LAMA

2.1. Why

LABA/LAMA combinations induce a potent, significant, and long-lasting relaxation of human medium bronchi and small airways undergoing cholinergic stimulation induced by acetylcholine, carbachol, and parasympathetic firing [1,7–10].

By a functional point of view, translational studies have demonstrated that the synergistic relaxant effect of LABA/LAMA combinations at the level of medium bronchi is related with an improvement in forced expiratory volume in 1 s (FEV₁) [9,10]. Conversely, the synergistic interaction on small airways may explain the beneficial impact on lung hyperinflation, leading to reduced dyspnea, improved exercise tolerance, and relief of symptoms [2,11].

Unlike LABA, the administration of LAMA alone does not modulate the intracellular synthesis of cyclic adenosine monophosphate (cAMP), a crucial intracellular messenger involved in the bronchorelaxant response. Conversely, when a LAMA is administered in combination with a LABA, the synthesis of cAMP is boosted into airway smooth muscle (ASM) [8]. Thus, the increased levels of cAMP induced by LABA/LAMA combinations may explain the synergistic inhibition of ASM contractility. Recent evidences also indicate that protein tyrosine kinases (PTKs) and K_Ca++ channels not only play a pivotal role in regulating the ASM contractility, but also modulate the synergic interaction between LABAs and LAMAs [13].

Additionally, several mechanisms that go beyond the ASM cell environment can regulate the LABA/LAMA interaction. For example, the synergy between LABAs and LAMAs has been supposed to be due to an inhibitory effect on the release of parasympathetic acetylcholine at prejunctional level, but recent findings have ruled out such a possibility [8].

The autonomic control of medium bronchi is mediated by the release of acetylcholine from vagal fibers, whereas the non-neuronal cholinergic system is prevalent at the level of small airways. Intriguingly, LABA/LAMA combinations inhibit the release of non-neurogenic acetylcholine from bronchial epithelium [8]. Despite the sparse distribution of vagal innervation at the level of bronchioles, muscarinic M₃ receptor is expressed along with β₂-AR in peripheral lung tissues. Thus, the impact of LABA/LAMA combinations against the release of non-neurogenic acetylcholine, together with their direct cross talk into the ASM cells, explains the strong synergism at the level of small airways [7,8].

The inhibitory effect of LABA/LAMA combinations on the non-neuronal cholinergic system may also explain the protective effect against COPD exacerbations, as reported by the FLAME study [15]. In fact, non-neurogenic acetylcholine plays a local auto/paracrine activity that modulate the innate mucosal defense mechanisms, the activity of C-sensitive sensory nerves, and inflammation [8].

2.2. When

The currently approved doses of LABA/LAMA FDCs warrant from 12 h to 24 h bronchodilation (once-daily FDCs: indacaterol/glycopyrronium 110/50 μg approved by European Medicines Agency [EMA]; olodaterol/tiotropium 5/5 μg approved by EMA, US Food Drug Administration [FDA], and Japanese Pharmaceuticals and Medical Devices Agency [PMDA]; vilanterol/umeclidinium 25/62.5 μg approved by EMA, FDA and PMDA; twice-daily FDCs: formoterol/aclidinium 12/400 μg approved by EMA; indacaterol/glycopyrronium 27.5/15.6 μg approved by FDA).

A correct regimen of administration should be selected by considering the intrinsic pharmacodynamic and pharmacokinetic characteristics of each monocomponent [3]. In particular, among LAMAs only tiotropium has been demonstrated to have a half-life at human muscarinic M₃ receptor longer than 24 h, whereas no pharmacological investigations have been carried out to assess the half-life of LABAs at human β₂-AR for more than 12 h [16,17]. Thus, by a strict pharmacological point of view, nowadays we still do not know whether the currently available once-daily LABA/LAMA FDCs adequately activate β₂-AR and antagonize muscarinic M₃ receptor over 24 h.

However, since the duration of action of bronchodilators is proportional to the dose, and considering that the regimen of administration of bronchodilation therapy is chosen by evaluating the duration of improvement of the change form baseline in FEV₁, the currently available FDCs improve lung function accordingly with their regimen of administration [14,18].

Nevertheless, we cannot omit that while EMA approved indacaterol/glycopyrronium at 110/50 μg as a once-daily FDC (EMA/CHMP/296722/2013), FDA approved the same dual combination as a twice-daily FDC, but at a reduced dosage (27.5/15.6 μg) (FDA Reference ID: 3840010). This suggests that adapting the doses of LABA/LAMA FDCs with the regimen of administration may guarantee an adequate level of pharmacological stenting of the airways.

The dual bronchodilation therapy has been endorsed in 2017 by the Global Strategy for the Diagnosis, Management and Prevention of COPD (GOLD 2017), which suggested to combine a LABA with a LABA in most COPD patients (GOLD groups B to D) [19]. Thus, LABA/LAMA FDCs should be administered to highly symptomatic patients regardless of the exacerbation history, and to patients with low symptoms and exacerbation history ≥2 or ≥1 leading to hospital admission.

COPD symptoms are characterized by circadian variability, with worsening in the early morning due to the reduction in airway caliber and increase in mucus secretion caused by the enhanced vagal tone during the night. Certainly, administering a once-daily LAMA in the evening may prevent the increase in cholinergic tone at night, and administering a LABA upon awakening may sustain the beneficial sympathetic tone in the morning. Unfortunately, this approach completely abrogates the interaction of dual bronchodilation. In fact, in order to elicit synergistic effects, it is essential that LABAs and LAMAs are administered in combination and at the same time, as a beneficial cross talk can be elicited only when the drugs mixture contemporary activate β₂-AR and inhibit muscarinic M₃ receptor also because the effect of stimulating the β₂-AR would be greater during postjunctional M₂ receptor inhibition, an inhibition that is transient [6]. Therefore, in those patients suffering from nightly and early morning symptoms, perhaps the twice-daily LABA/LAMA FDCs could be a more rational choice compared to the once-daily dual bronchodilation therapy. Moreover, combining a LABA with a LAMA synergistically improves the overall duration of bronchodilation, regardless of the duration of action of the monocomponents [7,8,20].

2.3. How

The main effort in the pharmacological characterization of the interaction between LABAs and LAMAs has been focused on the beneficial bronchorelaxant effect induced by the drug mixture. Nowadays, we can assert that the synergism elicited by dual bronchodilation therapy is an effect of class, and not specific for each LABA/LAMA combination [1,7–10,20]. Our studies have demonstrated that, in order to elicit an appreciable and significant bronchorelaxant synergism, LABAs and LAMAs must be combined at low isoeffective concentrations in the final drug mixture.

Overall, indirect evidences suggest that this condition is partially satisfied by formoterol/aclidinium (12/400 μg; concentration-ratio ∼1:33), and fully satisfied by indacaterol/glycopyrronium (110/50 μg and 27.5/15.6 μg; concentration-ratio ∼2:1) and olodaterol/tiotropium (5/5 μg; concentration-ratio ∼1:1) combinations when administered at low concentrations [8,9,20].

Conversely, recent clinical findings (GSK study/www.clinicaltrials.gov numbers: DB2116132/NCT02014480; DB2116133/NCT01716520) reported no synergistic bronchodilation for vilanterol/umeclidinium 25/62.5 μg (concentration ratio ∼1:2.5) [12]. We have defined such a peculiar condition a case of dose-combination dyscrasia, with vilanterol underdosed or vice versa umeclidinium overdosed [1]. In fact, when the concentration ratio between vilanterol and umeclidinium was correctly balanced in ex vivo experimental settings, strong to very strong synergistic bronchorelaxant effect was detected at low concentrations [1].

Moreover, considering that concerns about the potential additive fatal and nonfatal cardiovascular toxicity of LABAs and LAMAs in combination have arisen [21], the proved efficacy synergism can be exploited to reduce the dose of each monocomponent in the FDC by improving the safety profile while maintaining an acceptable level of clinical effectiveness.

Finally, but not less important, the new generation of inhaler devices have led to improved deposition of drug mixture into the lung periphery where, although the amount of drug mixture reaches lower concentrations than those in the central airways [22], LABA/LAMA FDCs can induce greater synergism with respect to larger bronchi [7,8].

3. Conclusions

LABA/LAMA combinations induce bronchorelaxant synergistic interaction when the drug mixture is well balanced and administered at low isoeffective concentrations. The overall approach of drug companies has been to combine in a FDC a LABA and a LAMA at the same doses for which the monocomponents were previously approved. Indeed, this practice does not permit to optimize the synergy in the final LABA/LAMA FDCs. Conversely, dose-finding studies are required to identify the correct dose ratio and establish the minimal doses for each monocomponent in the FDC, leading to the greater synergism with regard to the improvement in lung function, symptoms, and exacerbations.

Furthermore, although LABA/LAMA FDCs are characterized by an acceptable safety profile, the cardiovascular toxicity of LABAs and LAMAs may overlap. Thus, post-marketing surveillance, observational studies and well-designed meta-analyses are needed to assess the real risk of rare, but potentially serious, cardiovascular adverse events associated with the dual bronchodilation therapy in COPD patients.

Declaration of interest

L Calzetta has participated as an advisor in scientific meetings under the sponsorship of Boehringer Ingelheim and Novartis, has received non-financial support by AstraZeneca, received a research grant partially funded by Chiesi, Boehringer Ingelheim, Novartis, and Almirall, and is or has been a consultant to ABC Farmaceutici, Edmond Pharma, Zambon, Verona Pharma, and Ockham Biotech. MG Matera has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis, and has been a consultant for Chiesi. P Rogliani has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini Group, Mundipharma, and Novartis. M Cazzola has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini Group, Lallemand, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon, and has been a consultant to ABC Farmaceutici, Edmond Pharma, Chiesi, Lallemand, Novartis, Verona Pharma, and Zambon. Additionally, L Calzetta, P Rogliani and M Cazzola all work for a department that has received funding from Almirall, Boehringer Ingelheim, Chiesi, Novartis, and Zambon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

A reviewer on this manuscript has disclosed that they have received personal fees from Chiesi, Teva, GlaxoSmithKline, AstraZeneca, Mundipharma, Cipla, Sanofi, Sandoz, 3M and Zambon, and grants and personal fees from Boehringer Ingelheim, Novartis and Pfizer. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.