International Journal of Chronic Obstructive Pulmonary Disease Dovepress

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REVIEW

Nebulized Therapies in COPD: Past, Present, and

the Future
This article was published in the following Dove Press journal:
International Journal of Chronic Obstructive Pulmonary Disease

1 Abstract: Current guidelines recommend inhalation therapy as the preferred route of drug
Igor Z Barjaktarevic
Aaron P Milstone 2 administration for treating patients with chronic obstructive pulmonary disease (COPD).
1
Inhalation devices consist of nebulizers and handheld inhalers, such as dry-powder inhalers
Division of Pulmonary and Critical Care
Medicine, David Geffen School of (DPIs), pressurized metered-dose inhalers (pMDIs), and soft mist inhalers (SMIs). Although
Medicine at UCLA, Los Angeles, CA, pMDIs, DPIs and SMIs may be appropriate for most patients with COPD, certain patient
USA; 2Williamson Medical Center,
populations may have challenges with these devices. Patients who have cognitive, neuro-
Franklin, TN, USA
muscular, or ventilatory impairments (and receive limited assistance from caregivers), as
well as those with suboptimal peak inspiratory flow may not derive the full benefit from
handheld inhalers. A considerable number of patients are not capable of producing a peak
inspiratory flow rate to overcome the internal resistance of DPIs. Furthermore, patients may
have difficulty coordinating inhalation with device actuation, which is required for pMDIs
and SMIs. However, inhalation devices such as spacers and valved holding chambers can be
used with pMDIs to increase the efficiency of aerosol delivery. Nebulized treatment provides
patients with COPD an alternative administration route that avoids the need for inspiratory
flow, manual dexterity, or complex hand-breath coordination. The recent approval of two
nebulized long-acting muscarinic antagonists has added to the extensive range of nebulized
therapies in COPD. Furthermore, with the availability of quieter and more portable nebulizer
devices, nebulization may be a useful treatment option in the management of certain patient
populations with COPD. The aim of this narrative review was to highlight recent updates and
the treatment landscape in nebulized therapy and COPD. We first discuss the pathophysiol-
ogy of patients with COPD and inhalation device considerations. Second, we review the
updates on recently approved and newly marketed nebulized treatments, nebulized treat-
ments currently in development, and technological advances in nebulizer devices. Finally, we
discuss the current applications of nebulized therapy in patients with COPD.
Keywords: COPD, inhaler, nebulizer

Introduction
Chronic obstructive pulmonary disease (COPD) is a common, treatable, and preventable
disorder that is a significant cause of chronic morbidity and mortality. COPD is currently
ranked as the fourth leading cause of death in the US and is predicted to become the third
leading cause of death worldwide by 2030.1–4 More than 16.4 million people in the US
Correspondence: Aaron P Milstone have been diagnosed with COPD, but it is estimated that millions more have yet to be
Williamson Medical Center, diagnosed.4 The global COPD burden is projected to increase5 because of persistent
4323 Carothers Parkway, Suite 605,
Franklin, TN 37067, USA exposure to COPD risk factors, such as tobacco smoke and air pollution.6
Tel +1 615-790-4159
Fax +1 615-790-4158
Inhalation is the preferred administration route for COPD therapy due to the
Email amilstone@wmed.org high drug concentration that can be achieved locally within the lungs, leading to

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increased efficacy and decreased systemic adverse events conducting airways (eg, peribronchiolar fibrosis, mucus
(AEs) versus other administration routes (eg, oral or plugging) and loss of alveolar attachments because of
intravenous).7 Bronchodilation with muscarinic antago- emphysema, resulting in destabilization of these airways
nists, β-agonists, and inhaled corticosteroids (ICS) are related to decreased elastic recoil.12 Abnormal small air-
the foundation of pharmacological treatment in patients ways represent the main site of airflow resistance in
with COPD.6 These agents are commonly delivered COPD,5 and pharmacological targeting of the small air-
through nebulizers and handheld inhalers, which include ways remains one of the primary goals in the management
dry-powder inhalers (DPIs), pressurized metered-dose of COPD.
inhalers (pMDIs), and soft mist inhalers (SMIs). Direct delivery of pharmacological therapy via inhalation
Although Tashkin8 previously discussed innovations in is an attractive approach in pulmonary diseases because it
nebulized drug therapy and the role of nebulized therapy promotes high bioavailability of the therapeutic agent (10–200
in patients with COPD, there have been new important times greater than gastrointestinal delivery) and is independent
developments since his review was published. With the of dietary variability, extracellular enzymes, and interpatient
recent approval of the nebulized long-acting muscarinic metabolic differences that can affect gastrointestinal
antagonists (LAMAs) glycopyrrolate9 and revefenacin,10 absorption.13 Nevertheless, deposition of drug molecules into
as well as the current development of the first nebulized the lungs can be affected by particle and patient-related fac-
dual phosphodiesterase 3/4 inhibitor RPL554,11 treatment tors, such as airway geometry, airway humidity, particle size,
via nebulization represents an increasingly promising pathological processes affecting lumen patency of the airways,
alternative to handheld inhalers. breathing patterns, and lung clearance mechanisms.14
Thus, the aim of this narrative review was to highlight Consequently, these factors can influence the therapeutic
the recent updates and treatment landscape in nebulized effectiveness of inhaled therapies.14
therapy and COPD. We first discuss the pathophysiology Aerosol particle size is one of the most important deter-
of COPD and inhalation device considerations. Second, minants of drug deposition in the lungs.15 Each inhalation
we review the updates on recently approved and newly device has specificities on how to prepare the dose and
marketed nebulized treatments, nebulized treatments cur- deliver the drug into the airways, determining the consequent
rently in development, and technological advances in density and size of the particles generated (Figure 1).16
nebulizer devices. Finally, we discuss the current applica- Aerosol particle size is usually described based on mass
tions of nebulized therapy in patients with COPD. median aerodynamic diameter (MMAD), and the optimum
MMAD range is 1–5 µm.17 Some studies have suggested that
Selection of Articles for Review medium-sized particles (≈3 µm) may have higher efficacy for
In this narrative review, a PubMed search (prior to bronchodilation versus smaller particles.18 Inhalation devices
May 12, 2020) was conducted using numerous primary with a higher proportion of aerosol particles >5 µm in size
topic headings combined with appropriate terms for each emit doses less effectively and are associated with more
section of the article (eg, COPD + nebulizers or chronic oropharyngeal deposition and decreased lung delivery versus
obstructive pulmonary disease + nebulizers). The results of those with a smaller aerosol particle size and more efficient
the PubMed search were supplemented by relevant papers emission.19 The patient’s peak inspiratory flow rate (PIFR)
from reference lists of published articles. Relevant generally determines the velocity of the airborne particles,
ongoing and unpublished trials linked to nebulized treat- and this, in turn, also affects the probability of their impaction
ments were identified in the clinicaltrials.gov database. in the oropharynx and larynx.20 Therefore, optimizing drug
delivery requires the use of fine aerosol particles inhaled at
adequate flow rates, and a “one size fits all” approach may
Pathophysiology of COPD and
not be appropriate in the treatment of COPD.
Inhalation Device Considerations
Small airways disease is one of the key features of COPD.
The narrowing and destruction of small airways (<2 mm in Current Inhalation Delivery
diameter) characterizes early COPD and precedes the Systems
development of emphysema.12 Anatomical changes in Although pMDIs, DPIs, and SMIs may be appropriate for
these airways include structural abnormalities of the some patients with COPD, certain patient populations may

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Figure 1 The adult lung with dimensions and generations of the airways with predicted aerosol deposition.
Notes: Reprinted from European Journal of Pharmaceutical Sciences, Vol 49/edition number 5, Nahar K, Gupta N, Gauvin R, et al., In vitro, in vivo and ex vivo models for
studying particle deposition and drug absorption of inhaled pharmaceuticals, Pages No.805–818, Copyright (2013), with permission from Elsevier.16
Abbreviation: BSM, bronchial smooth muscle.

have challenges with these devices. Patients who have cog- and they still require a minimum PIFR of 20–30 L/min.19
nitive, neuromuscular, or ventilatory impairments (and Similar to breath-actuated pMDIs, DPIs require a minimum
receive limited assistance from caregivers), as well as those PIFR of 20–50 L/min.23 Women with shorter heights,
with suboptimal peak inspiratory flow, may not derive the patients with lower percent predicted forced vital capacity
full benefit of handheld inhalers.21,22 Regarding pMDIs, (FVC), and those with reduced inspiratory muscle strength
these patient populations may have difficulty coordinating are among the main patient groups that have suboptimal
inhaler activation with inspiration, struggle to produce a deep PIFR.24,25 Furthermore, generating a PIFR is dependent on
enough inhalation, inhale too quickly, and/or fail to hold their the patient’s respiratory muscle strength and level of effort,
breath for long enough for effective drug delivery. To over- which may be compromised in patients with COPD as
come some of the limitations associated with inadequate a result of an acute exacerbation, lung hyperinflation, hypox-
pMDI use, inhalation devices such as spacers and valved emia, and/or muscle wasting.26
holding chambers can be used with pMDIs to increase the For SMIs, coordination between patient actuation and
efficiency of aerosol delivery. Furthermore, breath-actuated inspiratory effort is reduced (but not completely elimi-
pMDIs are useful for patients who struggle to time their nated). Scintigraphic studies have shown that when com-
inspiration correctly.19 However, breath-actuated pMDIs do pared to a CFC-based pMDI, lung deposition with a soft
not help patients who stop inhaling at the time of actuation, mist inhaler is up to 50% higher, and oropharyngeal

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deposition is lower.27,28 However, a recent meta-analysis While some of the older nebulizer devices had some limita-
has reported that device use errors similar to those with tions (lack of portability, long administration times), advances
pMDIs occurred in approximately 60% of patients who in technology have led to the recent development of novel
used soft mist inhalers. The most common errors were nebulizers devices (breath-enhanced jet nebulizer, breath-
breathing errors, hand-breath coordination, and difficulties actuated jet nebulizer, and vibrating mesh nebulizers) that
with priming the inhalation device.29 reduce drug wastage and improve delivery efficiency (Figure
2). The key characteristics, advantages, and disadvantages of
Nebulized Drug Therapy these novel nebulizers’ devices are described in Table 1.37,38
A considerable number of patients with COPD who Breath-enhanced jet nebulizers (PARI LC® Sprint [PARI
remain breathless on high-dose pMDIs and DPIs derive Respiratory Equipment, Midlothian, VA], NebuTech HDN®
benefits from nebulized treatment.30 Nebulizers are an [Salter Labs, Arvin, CA], and SideStream Plus® [Philips,
appealing alternative to handheld inhalers for providing Murrysville, PA]) are designed to increase aerosol drug deliv-
inhaled therapy and have been the foundation of inhala- ery only during active inspiration and to expel the expired air
tion therapy in acute and critical care settings.31 outside of the device.37 Similarly, breath-actuated jet nebuli-
Nebulizers are now also widely used in clinics, out- zers, like the AeroEclipse® II BAN (Monaghan Medical
patient settings, and the home environment. Current Corporation, Plattsburgh, NY), also deliver aerosol only on
evidence suggests that the efficacy of treatments admi- inspiration and tend to decrease drug wastage during aerosol
nistered to patients with COPD via nebulizers is similar therapy.39 Vibrating mesh nebulizers, such as eFlow®rapid
to that observed in patients who used pMDIs and DPIs (PARI Pharma GmbH, Stranberg, Germany) and Micro Air®
with proper technique.32,33 Since nebulizers do not NE-U22 (Omron Healthcare, Bannockburn, IL), use micro-
require patient coordination between inhalation and pump technology for aerosol production and can produce
actuation or any special breathing technique (eg, a full aerosols with a fine-particle fraction, resulting in more efficient
exhalation followed by a full inhalation with a several- drug delivery when compared with conventional jet
second breath hold near total lung capacity), these nebulizers.40,41 The AKITA2® APIXNEB (PARI Pharma
devices are particularly beneficial in patients with cog- GmbH, Gräfelfing, Germany) mesh nebulizer uses an adaptive
nitive, neuromuscular, or ventilatory impairments and aerosol delivery technology that coordinates drug delivery
receive limited assistance from caregivers, as well as with the patient’s breathing pattern.42
those with suboptimal PIFR.21,22 More than 50% of Nebulizers are a form of aerosol generation and can be
patients who use nebulizers instead of other devices do used at any age or COPD stage. With recent technological
so because of physical or cognitive impairments.34 In advances, nebulizers will continue to play an important
terms of cost, reports on the use of nebulizers versus role in the management of COPD.
inhalers has shown varied financial impacts for hospi-
tals. A recent US retrospective analysis evaluated Overview of Nebulized
respiratory drug costs at 28 hospitals in the health sys-
Pharmacological Therapy
tem after a phased implementation of the inhaler to
A variety of nebulized short-acting and long-acting broncho-
nebulization protocol. Compared with pre-
dilators are available for the treatment of COPD. Overall, these
implementation, system-wide drug expenditures declined
nebulized therapies have demonstrated significant improve-
by approximately 40% in post-implementation years 1
ments in lung function and reduction in rescue medication use.
and 2.35 On the other hand, a cohort study at a single
US hospital showed that reducing nebulizer use, and
implementing MDIs in the hospital resulted in signifi-
Nebulized Short-Acting β-Agonists
cant savings annually. However, some limitations of this (SABAs) and Short-Acting Muscarinic
study included a lack of control group and possible Antagonists (SAMAs)
overestimation of cost-savings since some of the costs Nebulized short-acting bronchodilators are widely used for the
were semifixed.36 Taking into consideration the effec- management of patients with acute COPD exacerbations in the
tiveness in relation to the cost of therapy, a personalized hospital setting.43 Clinical studies of the nebulized SABAs
approach should be undertaken by healthcare personnel albuterol sulfate and levalbuterol hydrochloride have demon-
when treating their patients with COPD. strated improvements in forced expiratory volume in 1 second

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Breath-enhanced jet nebulizers

Pari LC® Sprint (PARI, Midlothian, VA) SideStream Plus® (Philips,Murrysville, PA)

Breath-actuated jet nebulizers

AeroEclipse® II (Monaghan Medical

Corporation, Plattsburgh, NY)

Vibrating mesh nebulizers

Micro Air® NE-U22 (Omron Healthcare, AKITA2® APIXNEB (PARI Pharma

Bannockburn, IL) GmbH, Gräfelfing, Germany)

Figure 2 Examples of novel marketed nebulizers. Examples of the different types of commercially available nebulizers that incorporate newer aerosol generating
technologies. PARI LC® Sprint ( PARI, USA83); SideStream Plus® (Philips, USA84); AeroEclipse® II (Monaghan Medical Corporation, USA85); Micro Air® NE-U22 ( Omron
Healthcare, USA86); AKITA2® APIXNEB (PARI Pharma GmbH, Germany87).

(FEV1) when compared with placebo.44,45 No significant differ- albuterol also demonstrated a mean time to peak FEV1 of 1.5
ences were observed between these two treatments in terms of hours, and the effect persisted for approximately 4 hours.48
efficacy, cost, occurrence of AEs, or hospitalizations.46 With
regard to nebulized SAMAs, nebulized ipratropium demon- Nebulized Long-Acting β-Agonists
strated significant improvements in FEV1 within 15–30 minutes, (LABAs)
which persisted for 4–5 hours.47 Furthermore, clinical studies of Nebulized arformoterol tartrate and formoterol are twice-
dual ipratropium-albuterol have demonstrated improvements in daily LABAs indicated for the maintenance treatment of
FEV1 versus both albuterol or ipratropium alone. Ipratropium- patients with COPD. Arformoterol demonstrated significant

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Table 1 Characteristics, Advantages, and Disadvantages of Nebulizers with Novel Technologies

Nebulizer Characteristics Advantages Disadvantages Examples
Type

Breath- 1. Air flows through the jet resulting in aero- 1. Drug delivery during 1. Sufficient flow required 1. PARI LC® Sprint
enhanced solization of the drug solution; powered by inhalation only, thus to initiate drug delivery NebuTech HDN®
JN compressor less drug wastage 2. Not ventilator-enabled SideStream Plus®
2. The additional room air carried into the 2. Easy to use and quiet 3. More expensive versus
nebulizer during inhalation causes conventional JNs and
aerosolization ultrasonic nebulizers
3. Drug solution cools during nebulization
4. Expired air vented outside of the device
5. Available as tabletop and portable models

Breath- 1. Air flows through the tube resulting in 1. Same as breath- 1. Same as breath-enhanced 1. AeroEclipse® II BAN
actuated JN aerosolization of the drug solution; pow- enhanced JN JN
ered by compressor
2. Aerosolization is triggered by patient
inhalation
3. Available as tabletop and portable models

Mesh 1. Piezoelectric crystals vibrate a mesh plate 1. Fast, quiet, portable, 1. Expensive 1. AKITA2®APIXNEB
nebulizer resulting in aerosolization and easy to use 2. Hard to clean 2. eFlow®rapid
2. Very fine droplets 2. Self-contained power 3. Medication dosage requires 3. Micro Air® NE-U22
3. No significant change in temperature of the source adjusting
solution during nebulization 3. Particle size optimized 4. Incompatible with vis-
4. Lower residual drug in chamber versus JNs for specific cous liquids or liquids
medications that crystallize on drying
4. More efficient when
compared other
nebulizers
Note: Data from these studies.37,38
Abbreviations: BAN, breath-actuated nebulizer; JN, jet nebulizer

improvements in mean percentage change FEV1 over safety profile in patients with moderate to severe COPD
12 weeks when compared with placebo and was well (Table 2).33,53-58
tolerated.49 A 12-month, Phase IV study demonstrated no In two 12-week Phase III trials (GOLDEN
increased risk of respiratory death or hospitalization related 3 [NCT02347761] and GOLDEN 4 [NCT02347774]), glyco-
to COPD exacerbations.50 Nebulized formoterol signifi- pyrrolate significantly improved FEV1 compared with placebo,
cantly increased trough FEV1 versus placebo over and the incidence of AEs was lowest among patients treated
12 weeks and had efficacy and safety profiles similar to with glycopyrrolate 25 µg twice daily in both Phase 3 trials.53
formoterol administered via a DPI.51 Discontinuations due to AEs were more common with placebo
versus glycopyrrolate, and the incidences of cardiovascular
Nebulized LAMAs AEs and major adverse cardiovascular events (MACEs) were
Glycopyrrolate bromide is a twice-daily inhalation solu- low in both trials. In a 48-week safety study (GOLDEN 5
tion that is administered via mesh nebulizer using the [NCT02276222]), the incidences of overall and serious AEs
eFlow® CS nebulizer (PARI Pharma GmbH, Stranberg, were similar among patients treated with glycopyrrolate or
Germany) and was approved in 2017 by the US Food tiotropium (active control); however, fewer MACEs were
and Drug Administration (FDA) for the maintenance treat- reported in patients who received glycopyrrolate.54
ment of COPD.9 The MMAD of glycopyrrolate/eFlow CS Revefenacin is a once-daily inhalation solution that is
is 3.7 µm, which is optimal for bronchodilation.18,52 administered via standard jet nebulizer using the PARI LC®
Overall, Phase III trials demonstrated that glycopyrrolate Sprint nebulizer (PARI Pharma GmbH, Starnberg, Germany)
significantly improves lung function and has an acceptable with a mouthpiece and the PARI Trek® S compressor (PARI

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Table 2 Efficacy and Safety of Nebulized LAMAs – Glycopyrrolate and Revefenacin

Reference Treatments and FEV1 (LS Mean Change from AE Incidence (%) SAE Incidence
Duration Baseline) (%)

Kerwin, 201753 GLY 25 µg GLY 25 µg: 105 mL; P<0.0001 GLY 25 µg: 39.6 4.6a
(GOLDEN 3; GLY 50 µg GLY 50 µg: 126 mL; P<0.0001 GLY 50 µg: 48.2
NCT02347761) PBO PBO: 52.3
12 weeks

Kerwin, 201753 GLY 25 µg GLY 25 µg: 84 mL; P<0.0001 GLY 25 µg: 47.2 4.2a
(GOLDEN 4; GLY 50 µg GLY 50 µg: 82 mL; P<0.0001 GLY 50 µg: 53.3
NCT02347774) PBO PBO: 52.4
12 weeks

Ferguson, 201754 GLY 50 µg GLY 50 µg: 102 mLb GLY 50 µg: 69.4 GLY 50 µg: 12.3
(GOLDEN 5; TIO 18 µg TIO 18 µg: 93 mL TIO 18 µg: 67.0 TIO 18 µg: 10.5
NCT02276222) 48 weeks

Ferguson, 201955 REV 175 µg REV 175 µg: 146 mL; P<0.0001 REV 175 µg: 51.0 REV 175 µg: 5.1
(Study 0126; REV 88 µg REV 88 µg: 79.2 mL; P<0.0003 REV 88 µg: 51.9 REV 88 µg: 4.7
NCT02459080) PBO PBO: 51.7 PBO: 6.7
12 weeks

Ferguson, 201955 REV 175 µg REV 175 µg: 147 mL; P<0.0001 REV 175 µg: 51.8 REV 175 µg: 2.5
(Study 0127; REV 88 µg REV 88 µg: 160.5 mL; P<0.0001 REV 88 µg: 56.6 REV 88 µg: 5.4
NCT02512510) PBO PBO: 46.9 PBO: 3.3
12 weeks

Donohue, 201956,57 REV 175 µg REV 175 µg: 52.3 mL; P<0.0003 REV 175 µg: 72.2 REV 175 µg: 12.8
(Study 0128; REV 88 µg REV 88 µg: 48.8 mL; P<0.0003 REV 88 µg: 74.7 REV 88 µg: 15.9
NCT02518139) TIO 18 µg TIO 18 µg: 91.5 mL; P<0.0003 TIO 18 µg: 77.2 TIO 18 µg: 16.3
52 weeks
33
Mahler, 2019 REV 175 µg REV 175 µg: 57.9 mLc REV 175 µg: 11.7 REV 175 µg: 0
(Study 0149; TIO 18 µg TIO 18 µg: 40.9 mL TIO 18 µg: 37.5 TIO 18 µg: 1
NCT03095456) 28 days

Siler, 201958 REV 175 µg/FOR 20 µg REV 175 µg/FOR 20 µg (seq): REV 175 µg/FOR 20 µg (seq): 4.8 NR
(Study 0167) PBO/FOR 20 µg 157.1 mL PBO/FOR 20 µg (seq): 11.9
42 days REV 175 µg/FOR 20 µg (combo): REV 175 µg/FOR 20 µg
115.6 mL (combo): 8.1
PBO/FOR 20 µg (combo): 10.9
Notes: The overall percentage of patients who experienced an SAE: The FEV1 changes between GLY and TIO were not significant: cThe FEV1 changes between REV and
a b

TIO were not significant.

Abbreviations: AE, adverse event; Combo, combined; FEV1, forced expiratory volume in 1 second; FOR, formoterol; GLY, glycopyrrolate; LS, least squares; NR, none
reported; PBO, placebo; REV, revefenacin; SAE, serious AE; Seq, sequential; TIO, tiotropium.

Respiratory Equipment, Midlothian, VA, USA).10 The In two 12-week Phase III trials (studies 0126
reported MMAD for the PARI LC® Sprint nebulizer/PARI [NCT02459080] and 0127 [NCT02512510]), revefenacin
Trek® S compressor is 3.8 µm, which is the optimal particle significantly improved trough FEV1 from baseline when
size for bronchodilation.18,52 Revefenacin was approved by compared with placebo, and the overall incidences of AEs
the FDA for the maintenance treatment of COPD in 2018.10 and serious AEs were similar in the revefenacin and pla-
Overall, Phase III trials demonstrated that revefenacin sig- cebo groups.55 The incidences of cardiovascular AEs and
nificantly improves lung function and has an acceptable MACEs were low.59 In a 52-week Phase III safety trial
safety profile in patients with moderate to very severe (study 0128 [NCT02518139]), revefenacin demonstrated
COPD (Table 2).33,55-58 significant improvement from baseline in trough FEV1,

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which was comparable with the improvement seen with Hyperglycemia was less frequent with nebulized budeso-
tiotropium (active control).56 The effect of revefenacin on nide than systemic corticosteroids.61
trough FEV1 in patients taking concomitant LABA ± ICS
was comparable with that in patients who were not taking Nebulized Antibiotics
these medications.56 AEs and serious AEs were compar- Some patients with COPD who have chronic bronchial infec-
able across all treatment groups.57 The incidences of car- tion may have an infective phenotype, and chronic infections
diovascular AEs and MACEs were low for all treatment are associated with exacerbations.62,63 Recent studies have
groups, with only one MACE (atrial fibrillation) consid- shown that regular use of some antibiotics may reduce
ered possibly/probably related to revefenacin 175 µg.59 In exacerbations.64–66 However, very little research has been
a 28-day Phase IIIb trial (study 0149 [NCT03095456]), done to date on nebulized antibiotics in the treatment of
revefenacin and tiotropium (active control) effectively COPD, with only four reports investigating the efficacy of
improved trough FEV1 and FVC from baseline with nebulized antibiotics in patients with COPD.67–70 Dal Negro
improvement numerically favoring revefenacin versus and colleagues evaluated the effect of nebulized tobramycin
tiotropium.33 In a prespecified subgroup analysis, revefe- (300 mg twice daily for 2 weeks) on the incidence of exacer-
nacin significantly improved trough FEV1 and FVC from bations and proinflammatory markers in patients with severe to
baseline compared with tiotropium in patients with severe very severe COPD who were colonized with Pseudomonas
to very severe COPD (ie, FEV1 <50% of predicted) who aeruginosa.68 Tobramycin decreased the incidence of exacer-
accounted for 80% of enrolled patients. Very few AEs bations by 42% when compared with the prior 6 months, and
were reported for revefenacin or tiotropium, and only proinflammatory markers were significantly reduced after
one serious AE (COPD exacerbation) was reported for 2 weeks of tobramycin. Soltaninejad and colleagues evaluated
tiotropium.33 In a 42-day Phase IIIb trial (study 0167 the effect of nebulized gentamycin (80 mg twice daily for 5
[NCT03573817]), the sequential and combination admin- days) versus placebo on lung function given in patients with
istration of revefenacin/formoterol via a standard jet nebu- acute exacerbations of COPD.70 Treatment with gentamicin
lizer was well tolerated versus placebo/formoterol, with resulted in significant improvements in FVC and FEV1 versus
fewer AEs associated with revefenacin/formoterol.58 placebo. Bruguera-Avila and colleagues evaluated the effect of
Revefenacin/formoterol (via sequential or combination nebulized colistin solution (80 mg twice daily for 1 year) on the
administration) demonstrated statistically significant number of severe exacerbations requiring hospitalizations and
improvements from baseline in trough FEV1 when com- on the length of hospitalizations in patients with COPD who
pared with placebo/formoterol.58 were colonized with P. aeruginosa.67 Colistin decreased the
number of hospitalizations from 2.0 to 0.9 per individual year,
and hospitalizations were shorter (23.3 vs 10.9 days). These
Nebulized ICS studies together suggest a potential therapeutic role for nebu-
GOLD recommends a LABA/ICS combination for initial lized antibiotics in patients with COPD who are colonized with
treatment in patients with frequent exacerbations and an resistant pathogens. However, a Phase II study evaluating the
eosinophil count >300 cells/µL or those with a history of efficacy of nebulized levofloxacin (240 mg twice daily for 5
asthma and COPD.6 Furthermore, patients who develop days every 28 days for 9–12 cycles) in patients with COPD at
exacerbations while on LAMA/LABA therapy may be high risk for exacerbations showed no significant decrease in
escalated to LABA/LAMA/ICS therapy. A recent report the exacerbation rate or an increase in the time to the next
indicated the benefits of triple inhaler therapy in COPD. exacerbation versus placebo.69 It was suspected that the
Triple therapy with fluticasone furoate, umeclidinium, and “pulsed” treatment regimen may have been suboptimal.69
vilanterol resulted in decreased moderate or severe COPD However, the impact of pulsed antibiotics remains uncertain
exacerbations and hospitalizations versus fluticasone furo- and requires further research.
ate/vilanterol or umeclidinium/vilanterol in patients with
COPD.60 To date, few studies have been conducted for Nebulized Therapy in Development
nebulized ICS treatment in patients with COPD. A meta- Rpl554
analysis indicated that high-dose nebulized budesonide RPL554 is a dual inhibitor of the phosphodiesterase
4–8 mg/day was noninferior to systemic corticosteroids 3 (PD3) and PD4 enzymes that is currently being devel-
on the change in FEV1 from baseline to end of treatment. oped in a nebulized formulation for maintenance treatment

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Dovepress Barjaktarevic and Milstone

of COPD and the treatment of acute exacerbations of demonstrated in 19–78% of outpatients and 32–52% of inpa-
COPD in the hospital setting. In four proof-of-concept tients before discharge from the hospital after treatment.23,77-
79
clinical studies, RPL554 demonstrated bronchodilator Two randomized controlled trials showed that patients
and anti-inflammatory effects and was well tolerated.11 with severe to very severe COPD and a suboptimal PIFR
In a single-dose, placebo-controlled, six-way crossover had greater improvements in lung function with a nebulized
Phase IIa study, nebulized RPL554 (6 mg) in addition to bronchodilator versus a DPI.33,80
standard doses of short-acting bronchodilators (salbutamol, For elderly patients and patients with arthritis, muscu-
ipratropium) produced significant and clinically meaningful loskeletal, or neurological conditions, dexterity and grip
additive bronchodilation (>60%; P<0.001) and was well strength should be considered when prescribing an inhala-
tolerated, with no increase in AEs versus placebo.71 In tion device. DPIs could be unsuitable for patients with
a 3-day, randomized, placebo-controlled Phase IIa study, tremors, as shaking or instability of the inhaler may lead
RPL554 (1.5 mg or 6 mg) in addition to tiotropium 18 µg to loss of the dose.81 Patients with reduced dexterity and
produced a statistically significant peak FEV1 (1.5 mg, weak grip strength may find it difficult to actuate a pMDI
104 mL, P=0.002; 6 mg, 127 mL, P<0.0001), and RPL554 device.21 Furthermore, coordination between inhalation
was well tolerated as add-on treatment to tiotropium.72 In and actuation is a common problem among these patients.
a 4-week, placebo-controlled Phase IIb study, RPL554 Nebulizers can overcome these concerns, and therefore,
demonstrated significant improvements in lung function may be suitable devices in these patient populations.
(>200 mL; P<0.001) and COPD symptoms (P≤0.002) and As stated by GOLD,6 LAMAs have a greater effect on
was shown to be well tolerated at all four doses (0.75 mg, the reduction of exacerbations and hospitalizations versus
1.5 mg, 3 mg, or 6 mg) when compared with placebo.73 LABAs. Before revefenacin and glycopyrrolate were
Together these studies demonstrate that RPL554 is approved, a nebulized LAMA was not available for main-
a promising treatment in COPD; however, further research tenance treatment of COPD to provide an alternative to
is required to determine its ability to elicit anti- inhalers. Revefenacin and glycopyrrolate demonstrated sig-
inflammatory activity in patients with COPD.74 RPL554 nificant improvements in lung function and have an accep-
is currently in Phase IIb development with Phase III trials table safety profile.33,53-59 Combination therapy with
planned in 2020. a LABA and a LAMA is recommended for patients with
very severe COPD who are highly symptomatic.6 No neb-
Discussion ulized fixed-dose LAMA/LABA combination is currently
Important factors to consider when evaluating inhalation on the market; however, a recent pilot study demonstrated
device options for patients with COPD include patient that the administration of revefenacin/formoterol via stan-
characteristics, drug combinations, and patient preference dard jet nebulizer was well tolerated compared with
and satisfaction. While inhalers pose various challenges placebo/formoterol.58 Furthermore, a recent study demon-
regarding effective delivery of therapies, nebulizers pro- strated that revefenacin was stable for at least 60 minutes at
vide patients with COPD an alternative administration room temperature when combined with either albuterol,
route that avoids the need for high inspiratory flow rates, arformoterol, or budesonide.82 Further research and devel-
manual dexterity, or complex hand-breath coordination. opment into a nebulized dual bronchodilator may be bene-
With the availability of quieter and more portable nebu- ficial from a patient compliance standpoint. In addition, the
lizer devices, patients should be able to administer nebulized benefits of triple therapy (LABA/LAMA/ICS) have been
treatment with minimum inconvenience. Despite some steps demonstrated. Triple therapy has the potential to further
that are generally involved with nebulizers (eg, assembly of decrease COPD exacerbations and hospitalizations versus
device, insertion of vial into device, and cleaning, which, in dual bronchodilator therapy (LABA/LAMA).60 The avail-
the case of the vibrating mesh nebulizer, requires disassem- ability of these bronchodilators via nebulization could cer-
bly of the device), patients are generally satisfied with nebu- tainly allow for concomitant delivery. The development of
lizers and consider these devices to be easy and convenient to the first nebulized PD3/4 inhibitor may provide another
use, as well as fast acting.75 A suboptimal PIFR (<60 L/min) treatment option for patients who develop further exacerba-
can identify patients who are more likely to have a less than tions on LABA/LAMA or LABA/LAMA/ICS.
favorable response to a DPI versus those with an optimal In conclusion, consideration of patient characteristics, drug
PIFR (≥60 L/min).76 Suboptimal PIFR has been combinations, and patient preference and satisfaction, is

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International Journal of Chronic Obstructive Pulmonary Disease 2020:15 1673
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Barjaktarevic and Milstone Dovepress

important when recommending and prescribing an inhalation 5. Mathers C, Loncar D. Projections of global mortality and burden of
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Medical writing support was funded by Theravance
a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients
Biopharma US, Inc. (South San Francisco, CA, USA) and with asthma or chronic obstructive pulmonary disease: findings from
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S2213-2600(13)70187-5
Gráinne Faherty, MPharm, for medical writing and Mary
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14. Labiris N, Dolovich M. Pulmonary drug delivery. Part I: physiological
Disclosure factors affecting therapeutic effectiveness of aerosolized medications.
Dr Igor Z Barjaktarevic has no relevant conflicts related to Br J Clin Pharmacol. 2003;56(6):588–599. doi:10.1046/j.1365-2125.
2003.01892.x
the subject of this review. He has consulted with Astra 15. Pleasants R, Hess D. Aerosol delivery devices for obstructive lung
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Healthcare, GlaxoSmithKline, Grifols, Mylan, Theravance models for studying particle deposition and drug absorption of
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research grants from AMGEN, GE Healthcare, Mylan and doi:10.1016/j.ejps.2013.06.004
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Theravance Biopharma. 2005;50(9):1209–1227.
Dr Aaron P Milstone has received speaking and con- 18. Usmani O, Biddiscombe M, Barnes P. Regional lung deposition and
bronchodilator response as a function of beta2-agonist particle size.
sulting fees from Boehringer Ingelheim, GlaxoSmithKline,
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