Adv Ther DOI 10.1007/s12325-014-0143-7

REVIEW

Pharmacological Consequences of Inhaled Drug Delivery to Small Airways in the Treatment of Asthma Anna Bodzenta-Łukaszyk • Marek Kokot

To view enhanced content go to www.advancesintherapy.com Received: June 6, 2014 Ó Springer Healthcare 2014

ABSTRACT

be administered to peripheral airways. This does

Small peripheral airways are an important target

not improve their efficacy and may increase their risk of cardiotoxicity. Thus, from a

for the anti-inflammatory treatment of asthma.

pharmacological point of view and the theory

To make anti-inflammatory drugs (inhaled corticosteroids [ICS]) effectively reach small

of aerosols’ deposition, fixed combinations of ICS and long-acting beta agonists are always

airways, they should be delivered inhalation techniques containing

using high

suboptimal. In many cases, the best solution may be to use fine-particle ciclesonide and a

proportions of fine or super-fine particles.

non-fine particle beta agonist administered

Higher proportions of fine particles are associated with higher systemic absorption of

from separate inhalers.

ICS leading to an increased risk of endogenous cortisol suppression. Ciclesonide, despite the highest proportion of fine and super-fine particle fractions, is the only ICS not associated with an increased risk of systemic adverse effects, including cortisol suppression. In contrary to ICS, bronchodilators should not Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0143-7) contains supplementary material, which is available to authorized users. A. Bodzenta-Łukaszyk (&) Clinical Department of Allergic and Internal Diseases, Medical University of Białystok, Bialystok, Poland e-mail: [email protected] M. Kokot Takeda Polska, Warsaw, Poland

Keywords: Asthma; Bronchodilators; Inhaled corticosteroids; Pharmacology of aerosols; Pulmonary deposition; Small airways; Systemic bioavailability of inhaled drugs

INTRODUCTION There

are

a

growing

number

of

reports

demonstrating that asthma phenotypes involving small airways are associated with increased severity, nocturnal symptoms, and frequent exacerbations [1–4]. It is commonly acknowledged that inflammation intensity is highest in small airways (\2 mm in diameter, generations 8–16) [5]. Recent reports indicate an

Adv Ther

association with the pathogenesis of bronchial

discuss

hyper-responsiveness

bronchial

pharmacodynamic consequences of inhalative

remodeling and obstruction of some terminal bronchioles due to recurrent

drugs peripherally deposited to the lung in asthma and the role of ciclesonide (CIC) in

bronchoconstriction and inflammation [6–8]. This phenomenon causes ventilation

that context.

heterogeneity

in

with

peripheral

airways

the

pharmacokinetic

and

with

binominal flow distribution, where bronchioles of normal patency are adjacent to

REVIEW

those with complete obstruction [9, 10]. The second argument supporting inhaled

This article is based on previously conducted

corticosteroids (ICS) delivery to peripheral

human or animal subjects performed by any of the authors.

airways is based on a general principle of pharmacodynamics which assumes that a drug’s effect is a result of its concentration at the site of action and the number of available active

receptors

(i.e.,

studies, and does not involve any new studies of

Are the Small Airways Best Reached by ‘Fine’ or ‘Extra Fine’ Particles?

glucocorticosteroid

receptors [GRs]). Considering this principle in the context of airway anatomy, it can be noted (e.g., on the basis of the Weibel model [11]) that the total cross-sectional area of the bronchial tree shows a linear increase after generation four of the airways and is multiple-fold higher than the cross-sectional area of the trachea. Thus, it is logical to assume that the dose of an inhaled drug reaching the segmental bronchi undergoes a several-fold ‘dilution’ over the increasing area of the respiratory epithelium during its delivery to the peripheral airways. This results in a reduction of drug concentration available for appropriate receptors regardless of their normal density in the given airway generation. On the other hand, authors have suggested that asthma involving small airways might be treated ineffectively using inhalation technologies due

conventional to the poor

peripheral penetration of ICS [12]. Thus, a mechanistic postulate has been raised to deliver anti-inflammation by new inhalation technique-driven drugs, predominantly to the peripheral airways, to provide more effective asthma treatment. The aim of this review is to

The physics of inhaled aerosols implies, that the more dispersed the aerosol, the more easily it will cross the natural barriers of the throat, and the higher the dose deposited in the lungs. Numerous experimental studies have revealed that

most

aerosolized

particles [5 lm

in

diameter are deposited in the oropharynx [12, 13]. The fraction of aerosol particles \5 lm in diameter has been termed fine-droplet or fineparticle fraction. The inhaled drugs containing higher mass proportions of such particles are called extra fine aerosols. These are characterized by higher pulmonary deposition compared to the conventional dry powder inhaler (DPI) or chlorofluorocarbon (CFC) containing metered-dose inhaler (MDI), which for the older devices was 8–12% of the emitted dose [14]. This fraction is also called the ‘‘respirable fraction’’, emphasizing the chance of particles \5 lm in diameter to be deposited in the lungs. The TurbuhalerÒ (TH; AstraZeneca ¨ derta¨lje, Sweden) was the first device that AB, So might be described as an extra fine inhaler. Its average pulmonary deposition is approximately twice that of older inhalers, although the

Adv Ther

total

Conversely, particles 2–6 lm in diameter

deposition of the emitted dose are variable

tend to easily penetrate the lungs and deposit

(18–35% of the nominal dose). The average depends on the patient’s inspiratory flow

in central airways [13]. The term ‘extra fine aerosol’ is often incorrectly treated as a

during inhalation and appropriate inhaler handling [15–18].

synonym of super-fine particle, and high deposition in small peripheral airways is

On the basis of mathematical and empirical

attributed to these particles. Nevertheless,

models of regional aerosol lung deposition [13] as a function of particle size, it should be noted

these terms are not interchangeable. This unclear definition has led to the wrong

that particles \0.1 lm in diameter (super-fine or ultra-fine particles) have excellent pulmonary

conclusion that all ‘extra fine’ aerosols increase peripheral drug deposition. Certainly,

penetration, and the highest chance to deposit

this may be the case if the aerosol contains large

in a small airway. A minor fraction (1–2 lm in diameter), present in most extra fine aerosols, is

numbers of super-fine particles, but this is not guaranteed for every inhalation technique.

less important for drug deposition in small airways as the resultant force responsible for

Particle mass distribution describes the contents of either extra fine or super-fine

those particles’ deposition on airway inner walls

particles in a given aerosol. The parameter

is negligible. Such particles, instead of being deposited in airways, reach the alveoli or are

commonly inhalation

exhaled (Fig. 1) [13].

aerodynamic diameter (MMAD); this is a particle diameter indicating the median mass

contents

of

fine

particles

and

the

used for comparing technologies is mass

various median

of aerosolized particles [19]. This isolated parameter of median distribution is not sufficient to estimate mass proportions of super-fine particles in the aerosol For a full characterization of the distribution of aerosol particles its geometric standard deviation must be known. Practically, there is a technical problem with accurately measuring the smallest particles. The use of laser technologies is required; hence, such direct measurements can only be performed in selected laboratories. It is easier, but less accurate, to perform these estimations Fig. 1 Conducting airways and alveolar deposition of aerosolized particles. The y-axis presents the probability of deposition in a given peripheral part of the airways and the x-axis presents the logarithmic particle size in micrometers. For the particles ranging from 0.1 to 1 the probability of airway deposition is near-zero, as the drug is either deposited in the alveoli or is completely exhaled during expiration [12, 28]. FP Fine particles (respirable particles), SFP super-fine particles

using cascade impactors [20]. From the point of view of pharmacological consequences of airway deposition of inhaled drugs, the studies using techniques that combine

scintigraphy

with

computed

tomography imaging (i.e., single-photon emission computed tomography), allowing for

Adv Ther

3D assessment of the inhaled drugs’ regional

indicate that it is unlikely that a technology

deposition in the airway, are more accurate.

unassociated with the side effect of losing the

Analyses of demonstrated to

studies have extent various

drug being exhaled (10% for the 3M technology, [2–3% for ModuliteÒ technology [Chiesi

inhalation technologies, often collectively termed as ‘extra fine’, differ regarding regional

Farmaceutici, Parma, Italy]) [25, 27] would be able to produce a significant mass of super-fine

drug deposition. These differences are as high as

particles.

50–80% of the delivered dose deposited in peripheral airways (Table 1) [22–25].

significant fraction of the exhaled radiolabelled drug is a tangible ‘marker’, able

For technology developed by 3M (3M Drug Delivery Systems, Northridge, CA, USA; e.g.,

to confirm the presence of super-fine particles with no direct laser measurements.

2D/3D what

The

scintigraphy

revealed

the

CIC hydrofluoroalkane [HFA]; Fig. 2), almost

It seems the 3M technology should be

half the mass of the inhaled aerosol is composed of particles \1 lm (MMAD = 1.1 lm), and,

termed ‘extra super-fine’ due to an increased mass of super-fine particles.

according to scintigraphy, *10% of the emitted dose is exhaled; thus, the super-fine

Pharmacological Consequences of Using

fraction comprises *27% of the emitted dose

Highly Dispersed Aerosols

[26]. This correlates well with the scintigraphic (3D) assessment of peripheral deposition result

Considering the above, it may be generally

of 29% [24]. Complied results of studies on particle

concluded that in optimal conditions the TH has twice the pulmonary deposition of older

distribution using 3D scintigraphy (Figs. 1, 2)

technologies. However, it is unclear to what

Table 1 Peripheral drug deposition in various inhalation technologies classified as ‘extra fine’ Brand name (nominal dose)

Delivered dose Total pulmonary of ICS (lg) deposition (%)

Peripheral deposition in scintigraphic 3D assessment (% of pulmonary deposition)

Peripheral dose (lg)

Symbicort Turbuhaler (100/6 lg)

80

32D

22a

5.9

Fostex Modulite (100/6 lg)

84.6

31N

34N

10.5

QVAR Easibreathe 3M (100 lg)

75

55D

45

18.5

Alvesco 3M (80 lg)

80

52D

45

18.7

The table was based on the data from the respective summaries of product characteristics and was supplemented with data from the literature only in cases where the characteristics lacked the relevant data [21]. Symbicort TurbuhalerÒ (AstraZeneca AB, So¨derta¨lje, Sweden); Fostex ModuliteÒ (Chiesi Farmaceutici, Parma, Italy); QVAR Easi-breatheÒ 3M (Teva UK Ltd., East Sussex, UK); Alvesco 3M (3M Drug Delivery Systems, Northridge, CA, USA) D percentage of delivered dose, N percentage of nominal dose, ICS inhaled corticosteroids a Calculated on the basis of 2D scintigraphy [22–25]

Adv Ther

Fig. 2 Sample distribution of aerodynamic diameters of particles of CIC-HFA, Batch No 4BGA001. In vitro study on Anderson Cascade Impactor (Takeda, data on file,

2001). CIC Ciclesonide, HFA hydrofluoroalkane, MMAD mass median aerodynamic diameter (for the delivered dose)

extent peripheral deposition increased. The newest 3M technology increases pulmonary

Leach et al. [14] and Harrison et al. [30] demonstrated that corticosteroid absorption

deposition of aerosolized drugs approximately 6-fold, and peripheral deposition [12-fold,

increased when administered in a highly dispersed form. A compilation of results of

thus, being much less ‘‘patient-dependent’’ [22, 25]. The properties of the Modulite technology

pharmacokinetic and deposition studies demonstrates a strong reverse correlation of

used in combination products are in between

pulmonary absorption of ICS and MMAD values

the TH and 3M technologies [24, 28]. Dolovich and Dhand [28] confirmed that by

(Fig. 3) [19, 31]. Since lungs are the principal source of

introducing corticosteroids (which are dissolved in HFA after adding small amounts of ethanol

active corticosteroids in the circulation, it can be assumed

[3M technology]), MDI aerosols gain new

increasing

properties and pulmonary drug deposition increases six- to eightfold. This increase

corticosteroids is associated with increased systemic absorption (total bioavailability)

allowed for a reduction of the drug dose by half, while maintaining similar efficacy of

and, probably, systemic effects. A comparative pharmacokinetic study of the

asthma control [29].

CFC

However, for the majority of inhaled drugs, the lungs do not stop active substances from

dipropionate (BDP-CFC) and the same active molecule formulated using 3M HFA technology

being absorbed directly to the systemic circulation while bypassing the liver (100%

(BDP-HFA) demonstrated how dispersion influences bioavailability of ICS. The study

lung bioavailability). Thus, a question has

revealed that changing BDP-CFC to BDP-HFA

arisen regarding how the ‘fine-particle’ characteristics of inhaled drugs affect total

results in a two- to threefold increase in bioavailability. When both formulations were

bioavailability.

compared in equipotential doses with respect to

dispersion

formulation

of

of

systemic that an

aerosolized

beclomethasone

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Fig. 3 Correlation of the pulmonary absorption of selected preparations of inhaled corticosteroids, (expressed as a proportion of the delivered dose) and the size of the aerosol particles indicated by their MMAD. Pearson correlation coefficient calculated by the author [19, 31]. BDP Beclomethasone dipropionate, BUD budesonide, CIC

ciclesonide, FL flunisolide FP fluticasone propionate, HFA hydrofluoroalkane, MMAD mass median aerodynamic diameter. Percentage of pulmonary-delivered dose represents amount of compound to be absorbed from the lungs

efficacy (2:1), bioavailability of BDP-HFA was still *50% higher [14, 29, 30].

deposition parameters

The first clinical studies (Thompson et al. [32]) comparing systemic pharmacodynamics of

excellent accuracy [34–37]. One hypothesis raised to explain this was

equivalent doses of both formulations regarding

based on the observation that corticosteroid

the function of the adrenal cortex seemed to suggest, contrary to these premises, that BDP-

solutions (HFA 3M) show higher absorption dynamics to the systemic circulation (shorter

HFA 3M at half the dose of the comparator had a better safety profile. Lipworth [33] suggested,

Tmax and higher Cmax) compared to suspended corticosteroid crystals, particularly when

on the basis of these results and his own

administered to peripheral areas of the lungs.

calculations, that BDP-HFA 3M, being equivalent in a mass proportion of 1:1 to

Hence, it was postulated that the influence of corticosteroids on the hypothalamic–pituitary

fluticasone propionate (FP) CFC/HFA, still has a lower inhibitory effect on the adrenal cortex.

axis is partially dependent on the absorption rate of biologically active substances, not only

and key pharmacokinetic of the corticosteroid, with

However, it remains unclear why these

on the dose absorbed [38, 39]. This suggests that

results and calculations were discordant with the estimations based on the widely accepted

a corticosteroid characterized by higher absorption dynamics would cause less adrenal

empirical pharmacokinetic/pharmacodynamic (PK/PD) formulas. These allow for the

suppression at a comparative systemic exposure (AUC0-inf).

prediction of relative suppression of cortisol

Unfortunately, an experimental comparison

secretion on the basis of the ICS dose,

of rapid and slow intravenous infusions of the

Adv Ther

same

dose

of

beclomethasone-17-

curve

describing

the

relationship

of

the

active

systemically absorbed dose and the decrease

metabolite of BDP) and measurements of adrenal function in healthy volunteers led to

of endogenous cortisol secretion [32, 41, 42, 44–46].

the complete rejection of such interpretations of the observed discrepancies [40]. Fowler et al.

Currently, the developmental barrier for ICS lies in the need for technologies which allow for

[41] demonstrated that a dose of 1,000 lg of an

the elimination of systemic effects of increased

inhaled corticosteroid in the BDP-HFA form (a ‘super-extra fine’ aerosol) caused significant

pulmonary absorption of small particle drugs. Essential progress was achieved by

suppression of the adrenal cortex as measured by the total urinary cortisol excretion versus

combining CIC with the 3M technology. CIC, introduced clinically 10 years ago, is a prodrug

placebo

monopropionate

(17-BMP;

an

(FP

which undergoes selective activation in the

formulated in HFA) in a suspension (not extra fine) form. FP has a longer serum half-life and

lungs (the active form is desisobutyrylciclesonide [des-CIC]). Steady-state pulmonary

*30% higher potency (relative affinity to GR) compared to BDP (17-BMP), however, due to a

concentrations are higher and more durable than its systemic concentrations, due to its

two-and-a-half fold lower systemic absorption

lipophilicity and ability to form reversible lipid

from the lungs and gastrointestinal tract (1% and 41%, respectively), FP appeared to show

conjugates [47, 48]. The key pharmacological benefits result from its increased binding to

better systemic safety when used in weightequivalent doses assumed to be equipotential

plasma proteins and rapid metabolism (both in the liver and in tissues; Table 3) [48–50].

[41]. When designing comparative studies of

After inhalation of CIC, only minimal amounts of des-CIC remain unbound to

various ICS using different inhalation systems,

plasma

with endpoints based on cortisol suppression, it is difficult to eliminate confounders. Thus, it

Moreover, it undergoes extensive hepatic and tissue metabolism to form inactive compounds

should be assumed that in practice it is more convenient to use models based on pulmonary

(Table 3) [51]. Experimental studies on healthy volunteers revealed that concentrations of des-

deposition

of

CIC in muscle and fat after the inhalation of

corticosteroids (PK/PD formulas; Table 2) [42]. Progress in inhalation technologies improves

supraclinical doses remained undetectable. This directly translates to the results of clinical

the deposition of ICS (both total and peripheral), enhancing efficacy which can

studies showing no significant effects of CIC on the adrenal cortex function with up to a

reduce doses by half. However, higher total

1,280 lg dose [52, 53].

deposition causes higher systemic absorption, and higher peripheral deposition causes further

Modern ICS should have high pulmonary (particularly peripheral) deposition

increase of pulmonary drug absorption [38]. Risk–benefit ratios of BDP-HFA vary in different

guaranteeing good penetration to the site of allergic inflammation with concomitant

studies. They improve in the lower dose range,

systemic safety. It should be pharmacologically

while they are less beneficial for higher doses because of the exponential upward segment of

characterized by its high proportion of the peripherally deposited fraction compared to

the conventional S-shaped pharmacodynamic

the circulating fraction unbound to plasma

and

versus

data

and

1,000 lg

FP-HFA

pharmacokinetics

proteins

and

available

to

tissues.

Adv Ther

Table 2 Calculated systemic absorptions and tissue-available fractions of ‘extra fine’ corticosteroids Brand name (nominal dose)

Delivered dose (lg)

Total bioavailability of the inhaled drug (%)

Symbicort TH (100/6 lg)

80

49D

10

3.9

Fostex Modulite (100/6 lg)

84.6

64Na

13b

8.3

QVAR Easi-breathe 3M (100 lg)

75

88D1

13

8.6

\1

0.4

Alvesco 3M (80lg)

80

51

D

Free serum fraction (%)

Tissue-available dose (lg)

The table was based on the data from the respective summaries of product characteristics and was supplemented with data from the literature only in cases where the characteristics lacked the relevant data [21]. 1From Agertoft et al. [42]. Doses of the drugs recognized as clinically equivalent (according to the GINA guidelines [43]). Symbicort TurbuhalerÒ (AstraZeneca AB, So¨derta¨lje, Sweden); Fostex ModuliteÒ (Chiesi Farmaceutici, Parma, Italy); QVAR Easi-breatheÒ 3M (Teva UK Ltd., East Sussex, UK); Alvesco 3M (3M Drug Delivery Systems, Northridge, CA, USA) N percentage of nominal dose, D percentage of delivered dose, BDP beclomethasone dipropionate, 17-BMP beclomethasone monopropionate a Pooled BDP and 17-BMP b For BDP, no data are available for 17-BMP

Table 3 Selected pharmacokinetic properties of inhaled corticosteroids (key biologically active metabolites) that are decisive for the tissue drug concentrations and its systemic adverse effects Inhaled corticosteroid

Gastrointestinal absorption (%)

Fraction unbound to plasma proteins (%)

Clearance of the active compound (L/min)

BDP/17-BMP

41

13/NA

120 60–90

FP

\1

10

des-CIC

\1

\1

228

11

12

84

BUD

Adapted from Winkler et al. [51] and the respective summaries of product characteristics [21] 17-BMP beclomethasone-17-monopropionate, BDP beclomethasone dipropionate, BUD desisobutyryl-ciclesonide, FP fluticasone propionate, NA not applicable

budesonide,

des-CIC

proteins. In this respect, CIC-HFA is the anti-

efficacy, particularly refractory asthma, has

inflammatory therapy with the most favorable therapeutic index (Fig. 4).

become less controversial [54, 55]. Contrary to ICS, the use of ‘extra fine’ formulations of beta agonists

Is Administration of Bronchodilators to the Small Airways Desirable?

and

anticholinergic

drugs

seems

pointless. There is no theoretical basis for delivering bronchodilators to ‘small airways’

dispersed

since it is well known that, in the peripheral airways the muscularis propria becomes

corticosteroids in improving asthma treatment

thinner, and the receptors responsible for

Over

time,

the

role

of

highly

Adv Ther

Fig. 4 A pharmacological index of the corticosteroids classified as ‘extra fine’ formulations expressed by the proportion of the dose deposited in the peripheral parts of the lungs (small airways) to the absorbed dose available to the tissues (unbound to proteins). The delivered (emitted) doses of the corticosteroids were similar. The calculations were performed by the author. The solid line represents the situation when an increase of the fraction of corticosteroid

reaching the small airways proportionally increases the systemic risk. For each corticosteroid the area below this line represents a better index and the area above this line represents a worse index. See also Tables 1 and 2. Lower right quadrant includes the drugs characterized by an increased deposition in small airways with a concomitant decrease of systemic risk (ciclesonide hydrofluoroalkane)

bronchodilation are located predominantly in

lowest

the central airways [56].

bronchodilation

In 1996, Zanen et al. [57] used monodispersed aerosols of salbutamol and

commercial inhalers and monodispersed aerosols with 6 lm particles that had the

ipratropium bromide to demonstrate the optimal aerosol dispersion (3 lm) at which

lowest peripheral deposition. Long-acting beta agonists (LABA) undergo

improvement

almost

of

ventilation

parameters

bronchodilation.

complete

was

The

best

achieved

using

absorption

via

the

(including the so-called small airway tests) was highest and concluded that highly dispersed

gastrointestinal system or the lungs. Therefore, it is assumed that the total increase of

aerosols of these agents caused the lowest bronchodilation.

pulmonary deposition of a drug resulting from the use of a highly dispersed aerosol does not

Similar effects were observed by Usmani

increase total systemic drug exposure (AUC).

who compared scintigraphic of drug deposition and

However, it should be noted that the dynamics of pulmonary drug absorption are altered,

improvements of lung function in asthma patients receiving monodispersed aerosols of

leading to an increase of Cmax and a reduction in the time taken to achieve this (Tmax).

salbutamol (1.5, 3, and 6 lm) and commercial polydispersed salbutamol administered via

Although general toxicity of ICS is not dependent on absorption dynamics, cardiac

MDI. Peripheral deposition was highest for

toxicity,

particles 1.5 lm in diameter, also causing the

arythmogenicity of some beta agonists [59, 60]

et al. [58] assessments

particularly

the

well-known

Adv Ther

and anticholinergics [61–64], depends on peak

components

drug

absorption in the coronary circulation.

concentrations

in

the

coronary

and

easier

pulmonary

drug

circulation. The drug is absorbed directly in the circulation and does not pass through the

Nevertheless, as argued by enthusiasts, combination products are convenient to use,

liver. Drug concentrations, immediately after inhalation, are high in the coronary circulation.

which may translate into better compliance and adherence, which are important elements of

Moreover, it should be noted that in some

asthma treatment [66, 67].

patients, long-term exposure to high doses of LABA increases the risk of severe exacerbations

Table 4 compares highly dispersed combination products (Modulite technology)

of asthma and/or death from asthma [65].

with those administered using separate inhalers (CIC 3M plus formoterol HFA Modulite). A

Combination Products and the Pharmacology of Aerosols

comparison

Although ICS/LABA fixed-combination products have recently gained popularity, they

and/or organ-specific adverse effects [24, 68, 69].

are suboptimal compared with aerosols’ pharmacology perspective. They are actually a

The table demonstrates that CIC 3M and

of

formoterol

deposition

and

absorbed tissue-available fractions is shown. These are the key factors influencing systemic

compromise between a low-dispersion mixture

Modulite formoterol administered from separate MDI-HFA inhalers, compared with the

that does not deliver the anti-inflammatory drug to the peripheral airways, or a highly

fixed BDP/formoterol combination using HFA Modulite technology, require less inhalations

dispersed mixture that poses extra risks related to increased bioavailability of one or both

per day (three and four, respectively; Table 4). Moreover, the fixed combination is associated

Table 4 Pharmacokinetic consequences of the administration of comparable peripheral doses of inhaled corticosteroids in a form of a fixed BDP/Fo combination product or CIC plus Fo in separate hydrofluoroalkane metered-dose inhalers Peripheral deposition (%)

Peripheral pulmonary ICS dose/LABA dose absorbed directly from the lungs (lg)

Number of inhalations ensuring comparable ICS deposition in the small airways

Theoretical systemic exposure with a comparable ICS deposition in the small airways (lg)

BDP (100 lg) 31

34

10.5

4

238.3

Fo (6 lg)

31

34

CIC (160 lg) 52

47

39.1

1

83.2

Fo (12 lg)

NA

?

2

18.8a

Fixed combination/ drugs in separate inhalers

Total pulmonary deposition (% of nominal dose)

31

18.0a

0.63

The table is based on the data from respective summaries of product characteristics and data from the literature [69–71]. The delivered dose for the BDP (Actimos, Chiesi Farmaceutici, Parma, Italy) was 10.1 lg (according to the summary of product characteristics) and 5 lg for the Fostex product (Chiesi Farmaceutici, Parma, Italy). Gastrointestinal bioavailability of all presented products was taken into account BDP beclomethasone dipropionate, CIC ciclesonide, Fo formoterol, ICS inhaled corticosteroid, LABA long-acting beta agonists, NA not applicable a Assuming *90% bioavailability after the administration of inhaled Fo. Calculations by the author

Adv Ther

with a fourfold higher total systemic absorption

better to use ICS and LABA from separate

of the corticosteroid (not taking any unbound

inhalers to maximize pulmonary deposition of

fraction into account). Thus, long-term administration of a fixed combination of

corticosteroids without increasing peripheral deposition of beta agonists, and without

extra fine formulations is associated with increased systemic risk, and shows no

increasing systemic effects potentially caused by both components. Moreover, it seems that

superiority

CIC

over

traditional

approaches

combined

with

various

appropriately

regarding convenience. Furthermore, practitioners prescribing CIC and formoterol

selected bronchodilators is the safest and most effective treatment of asthma [71–74],

in separate inhalers retain the possibility of flexible dosages based on patients’ needs, and

particularly in difficult clinical situations, as well as for all levels of severity of the disease.

better control of formoterol usage (e.g., [24 lg of formoterol per day is not always necessary) [24, 68, 69].

ACKNOWLEDGMENTS

Combining CIC with another ‘non-extra fine’ LABA (salmeterol) or with formoterol

We thank Proper Medical Writing Sp. z o.o.

administered via DPI, may decrease cardiac risks by reducing drug absorption in coronary circulation (and the potential effects of formoterol on the QT interval) [70]. Conversely, a good solution for practitioners and patients attached to the idea of using fixed ICS/LABA combinations is the temporary addition of extra doses of CIC rather than increasing the dosage of the combination products.

CONCLUSION

which provided medical writing services and was funded by Takeda Poland. No other funding or sponsorship was received for this study or publication of this article. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. Conflict of interest. Anna BodzentaŁukaszyk gave the lectures upon request of Takeda, Novartis, and Hal Allergy companies. Marek Kokot is a current Takeda Polska employee.

Pharmacologically, administering ICS to small airways seems justified by the pathophysiology and clinical course of asthma, particularly refractory asthma. However, the delivery of ‘conventional’ ICS to peripheral airways increases the risk of systemic adverse effects.

Compliance with ethics guidelines. This article

is

based

on

previously

conducted

studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

CIC in the 3M formulation is the only corticosteroid not causing increased systemic exposure to peripheral tissues, despite its high deposition in peripheral lung areas. Inhaled fixed combinations are always a compromise. Thus, sometimes in clinical practice it might be

REFERENCES 1.

Farah CS, King GG, Brown NJ, et al. The role of the small airways in the clinical expression of asthma in adults. J Allergy Clin Immunol. 2012;129:381–7.

Adv Ther

2.

van der Wiel E, ten Hacken NH, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review. J Allergy Clin Immunol. 2013;131:646–57.

16. Tarsin WY, Pearson SB, Assi KH, Chrystyn H. Emitted dose estimates from Seretide Diskus and Symbicort Turbuhaler following inhalation by severe asthmatics. Int J Pharm. 2006;316: 131–7.

3.

Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol. 2002;109(Suppl 2):447–60.

17. Delvadia R, Hindle M, Longest PW, Byron PR. In vitro tests for aerosol deposition II: IVIVCs for different powder inhalers in normal adults. J Aero Med Pulm Drug Deliv. 2012;26:138–44.

4.

Morrison JF, Pearson SB. The parasympathetic nervous system and the diurnal variation of lung mechanics in asthma. Respir Med. 1991;85:285–9.

5.

6.

7.

Hamid Q. Pathogenesis of small airways in asthma. Respiration. 2012;84:4–11. Downie SR, Salome ChM, Verbanck S, Thompson B, Berend N, King GG. Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation. Thorax. 2007;62:684–9. Wiggs BR, Hrousis CA, Drazen JM, Kamm RD. On the mechanism of mucosal folding in normal and asthmatic airways. J Appl Physiol. 1997;83:1814–21.

8.

Grainge CL, Lau LC, Ward JA, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364:2006–15.

9.

Venegas JG, Winkler T, Musch G, et al. Selforganized patchiness in asthma as a prelude to catastrophic shifts. Nature. 2005;434:777–82.

10. Gonem S, Natarajan S, Hartley R, et al. Cluster analysis reveals a distinct small airway- predominant phenotype of asthma. Thorax. 2012;67:A7. 11. Weibel ER. Morphometry of the human lung. New York: Academic; 1963. _ ´ ski P, 12. Fal AM, Nizankowska-Mogilnicka E, S´liwin Emeryk A, Antczak A, Kruszewski J. Drobne drogi oddechowe w chorobach obturacyjnych płuc. Pneumol Alergol Pol. 2012;80:146–51. 13. Heyder J. Deposition of inhaled particles in the human respiratory tract and consequences for regional targeting in respiratory drug delivery. Proc Am Thorac Soc. 2004;1:315–20. 14. Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFAbeclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J. 1998;12:1346–53. 15. Borgstrom L. Deposition patterns with Turbuhaler. J Aerosol Med. 1994;7(Suppl 1):S49–53.

18. Tamura G, Sakae H, Fujino S. In vitro evaluation of dry powder inhaler devices of corticosteroid preparations. Allerg Int. 2012;61:149–54. 19. Buhl R. Local oropharyngeal side effects of inhaled corticosteroids in patients with asthma. Allergy. 2006;61:518–26. 20. Taki M, Marriott C, Zeng XM, Martin GP. Aerodynamic deposition of combination of dry power inhaler in vitro: a comparison of three impactors. Int J Pharm. 2010;388:40–51. 21. The Electronic Medicines Compendium (eMC). http://www.medicines.org.uk/emc/. Accessed July 28, 2014. 22. Newman SP, Pitcairn GR, Hirst PH, et al. Scintigraphic comparison of budesonide deposition from two dry powder inhalers. Eur Respir J. 2000;16:178–83. 23. Hirst PH, Bacon RE, Pitcairn GR, Silvasti M, Newman SP. A comparison of the lung deposition of budesonide from Easyhaler, Turbuhaler and pMDI plus spacer in asthmatic patients. Respir Med. 2001;95:720–7. 24. De Backer W, Devolder A, Poli G, et al. Lung deposition of BDP/Formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J Aerosol Med Pulm Drug Deliv. 2010;23:137–48. 25. Newman S, Salmon A, Nave R, Drollmann A. High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respir Med. 2006;100:375–84. 26. Nave R, Mueller H. From inhaler to lung: clinical implications of the formulations of ciclesonide and other inhaled drugs. Int J Gen Med. 2013;6:99–107. 27. Dalby NR, Eicher J, Zierenberg B. Development of Respimat Soft Mist Inhaler and its utility in respiratory disorders. Med Devices (Auckl). 2011;4:145–55. 28. Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet. 2011;377:1032–45.

Adv Ther

29. Busse WW, Brazinsky S, Jacobson K, et al. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol. 1999;104:1215–22.

41. Fowler SJ, Orr LC, Wilson AM, Sims EJ, Lipworth BJ. Dose-response for adrenal suppression with hydrofluoroalkane formulations of fluticasone propionate and beclomethasone dipropionate. J Clin Pharmacol. 2001;52:93–5.

30. Harrison LI, Soria I, Cline AC, Ekholm BP. Pharmacokinetic differences between chlorofluorocarbon and chlorofluorocarbon-free metered dose inhalers of beclomethasone dipropionate in adult asthmatics. J Pharm Pharmacol. 1999;51:1235–40.

42. Agertoft L, Laulund LW, Harrison LI, Pedersen S. Influence of particle size on lung deposition and pharmacokinetics of beclomethasone dipropionate in children. Pediatr Pulmonol. 2003;35:192–9.

31. Martin RJ, Szefler SJ, Chinchilli VM, et al. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med. 2002;165:1377–83. 32. Thompson PJ, Davies RJ, Young WF, Grossman AB, Donnell D. Safety of hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol. Respir Med. 1998;92(Suppl A):33–9.

43. GINA—Global initiative for asthma. http://www. ginasthma.org/. Accessed July 28, 2014. 44. Van Schayck CP, Donnell D. The efficacy and safety of QVAR (hydrofluoroalkane-beclometasone dipropionate extrafine aerosol) in asthma (part 1): an update of clinical experience in adults. Int J Clin Pract. 2004;58:678–88.

33. Lipworth BJ. The comparative safety/efficacy ratio of HFA-BDP. Respir Med. 2000;94(Suppl D):S21–6.

45. Van Schayck CP, Donnell D. The efficacy and safety of QVAR (hydrofluoroalkane-beclometasone dipropionate extrafine aerosol) in asthma (part 2): an update of clinical experience in children. Int J Clin Pract. 2004;58:786–94.

34. Derendorf H. Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in relation to efficacy and safety. Respir Med. 1997;91(Suppl A):22–8.

46. Currie GP, Fowler SJ, Wilson AM, Sims EJ, Orr LC, Lipworth BJ. Airway and systemic effects of hydrofluoroalkane fluticasone and beclomethasone in patients with asthma. Thorax. 2002;57:865–8.

¨ llmann 35. Derendorf H, Hochhaus G, Meibohm B, Mo H, Barth J. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids. J Allergy Clin Immunol. 1998;101:S440–6.

47. Rohatagi S, Arya V, Zech K, et al. Population pharmacokinetics and pharmacodynamics of ciclesonide. J Clin Pharmacol. 2003;43:365–78.

36. Hubner M, Hochhaus G, Derendorf H. Comparative pharmacology, bioavailability, pharmacokinetics, and pharmacodynamics of inhaled glucocorticoids. Immunol Allergy Clin North Am. 2005;25:469–88. 37. Webner B, Hochhaus G. A pharmacokinetic simulation tool for inhaled corticosteroids. AAPS J. 2013;15:159–71. 38. Freiwald M, Valotis A, Kirschbaum A, et al. Monitoring the initial pulmonary absorption of two different beclomethasone dipropionate aerosols employing a human lung reperfusion model. Respir Res. 2005;6:21. 39. Dekhuijzen PN, Honour JW. Inhaled corticosteroids and the hypothalamic-pituitary-adrenal (HPA) axis: do we understand their interaction? Respir Med. 2000;94:627–31. 40. Mulrennan SA, Hogg JS, Teoh RC, Morice AH. Adrenal axis suppression unrelated to the dynamics of dosing with beclomethasone monopropionate. Br J Clin Pharmacol. 2006;63:288–91.

48. Rohatagi S, Appajosyula S, Derendorf H, et al. Riskbenefit value of inhaled glucocorticoids: a pharmacokinetic/pharmacodynamic perspective. J Clin Pharmacol. 2004;44:37–47. 49. Rohatagi S, Luo Y, Shen L, et al. Protein binding and its potential for eliciting minimal side effects with a novel inhaled corticosteroid, ciclesonide. Am J Ther. 2005;12:201–9. 50. Xu J, Nave R, Lahu G, Derom E, Derendorf H. Population pharmacokinetics and pharmacodynamics of inhaled ciclesonide and fluticasone propionate in patients with persistent asthma. J Ciln Pharmacol. 2010;50:1118–27. 51. Winkler J, Hochaus G, Derendorf H. How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc. 2004;1:356–63. 52. Szefler S, Rohatagi S, Williams J, Lloyd M, Kundu S, Banerji D. Ciclesonide, a novel inhaled steroid, does not affect hypothalamic-pituitary-adrenal axis function in patients with moderate-to-severe persistent asthma. Chest. 2005;128:1104–14.

Adv Ther

53. Bateman ED. Efficacy and safety of high-dose ciclesonide for the treatment of severe asthma. Expert Rev Respir Med. 2013;7:339–48. 54. Gentile DA, Skoner DP. New asthma drugs: small molecule inhaled corticosteroids. Curr Opin Pharmacol. 2010;10:260–5. 55. van den Berge M, ten Hacken NH, van der Wiel E, Postma DS. Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma. Allergy. 2013;68:16–26.

65. Salpeter SR, Wall AJ, Buckley NS. Long-acting Betaagonists with and without inhaled corticosteroids and catastrophic asthma events. Am J Med. 2010;123:322–8. 66. Breekveldt-Postma NS, Koerselman J, Erkens JA, et al. Treatment with inhaled corticosteroids in asthma is too often discontinued. Pharmacoepidemiol Drug Saf. 2008;17:411–22.

56. Howarth PH. Why particle size should affect clinical response to inhaled therapy. J Aerosol Med. 2001;14(Suppl 1):S27–34.

67. Perrin K, Williams M, Wijesinghe M, James K, Weatherall M, Beasley R. Randomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting b-agonist inhaler therapy in asthma. J Allergy Clin Immunol. 2010;126:505–10.

57. Zanen P, Go LT, Lammers JW. Optimal particle size for beta 2 agonist and anticholinergic aerosols in patients with severe airflow obstruction. Thorax. 1996;51:977–80.

68. Paggiaro P, Nicolini G, Papi A. Extrafine beclomethasone dipropionate/formoterol hydrofluoroalkane-propelled inhaler in asthma. Expert Rev Resp Med. 2008;292:161–6.

58. Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition and bronchodilator response as a function of b2-agonist particle size. Am J Respir Crit Care Med. 2005;172:1497–504.

69. Ha¨ussermann S, Acerbi D, Brand P, et al. Lung deposition of formoterol HFA (AtimosÒ/ForairÒ) in healthy volunteers, asthmatic and COPD patients. J Aerosol Med. 2007;20:331–41.

59. Warnier MJ, Rutten FH, Kors JA, et al. Cardiac arrhythmias in adult patients with asthma. J Asthma. 2012;49:942–6.

70. Bremner P, Woodman K, Burgess C, et al. A comparison of the cardiovascular and metabolic effects of formoterol, salbutamol and fenoterol. Eur Respir J. 1993;6:204–10.

60. Desantiago J, Ai X, Islam M, et al. Arrhythmogenic effects of beta2-adrenergic stimulation in the failing heart are attributable to enhanced sarcoplasmic reticulum Ca load. Circ Res. 2008;102:1389–97. 61. Singh S, Loke YK, Enright P, Furberg CD. Proarrhythmic and pro-ischemic effects of inhaled anticholinergic medications. Thorax. 2013;68:114–6. 62. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomized controlled trials. BMJ. 2011;342:d3215. 63. Mathioudakis AG, Mathioudakis GA. Tiotropium inhaler devices: seeking convenience when mortality is at stake? J Aerosol Med Pulm Drug Deliv. 2013;26:120. 64. Wise RA, Anzueto A, Cotton D, et al. Tiotropium respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369:1491–501.

71. O’Connor BJ, Kilfeather S, Cheung D, et al. Efficacy and safety of ciclesonide in patients with severe asthma: a 12-week, double-blind, randomized, parallel-group study with long-term (1-year) follow-up. Expert Opin Pharmacother. 2010;11:2791–803. 72. Cohen J, Postma DS, Douma WR, Vonk JM, De Boer AH, ten Hacken NH. Particle size matters: diagnostics and treatment of small airways involvement in asthma. Eur Respir J. 2011;37:532–40. 73. Hoshino M. Comparison of effectiveness in ciclesonide and fluticasone propionate on small airway function in mild asthma. Allergol Int. 2010;59:59–66. 74. Derom E, Louis R, Tiesler C, Engelsta¨tter R, Kaufman JM, Joos GF. Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma. Eur Respir J. 2009;33:1277–86.