Immunol Allergy Clin N Am

25 (2005) 469 488

Comparative Pharmacology, Bioavailability,

Pharmacokinetics, and Pharmacodynamics of
Inhaled Glucocorticosteroids
Melanie Hqbner, B Pharm, Gqnther Hochhaus, PhD,
Hartmut Derendorf, PhD*
Department of Pharmaceutics, University of Florida, College of Pharmacy, Box 100494, JHMHC,
Gainesville, FL 32610, USA

Glucocorticoids are important anti-inflammatory substances that play a major

role in the treatment of local and systemic inflammations. Knowledge about the
pharmacokinetics and pharmacodynamics of the different available glucocorticoids is necessary to assess their efficacy and safety profile.
Inhaled corticosteroids are mainly used as first-line treatment for patients who
have persistent asthma because they exert a local effect at the site of action and
thus decrease the risk for adverse drug reactions. Currently there are seven
different corticosteroids on the market that are widely used for the treatment of
asthma. To compare the different available inhaled glucocorticosteroids for the
treatment of asthma, it is important to understand the different structures and their
pharmacokinetic and pharmacodynamic parameters. An explanation of the
differences between the marketed inhaled corticosteroids should help to identify
the pharmacologic properties that are responsible for an optimum pharmaceutic
asthma treatment.
Asthma is a severe disease that becomes increasingly problematic. Approximately 10.6% of adults and 12.5% of children are currently suffering from
asthma in the United States and more than 4000 deaths per year occur because of
asthma [1].
Asthma is a chronic inflammation of the airway tissue that is usually
accompanied by an allergic reaction to antigens. It is characterized by an increase

* Corresponding author.
E-mail address: hartmut@cop.ufl.edu (H. Derendorf).
0889-8561/05/$ see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.iac.2005.05.004
immunology.theclinics.com

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hUbner et al

of T lymphocytes and B cells. Antigen-presenting cells (alveolar macrophages)

are stimulated by IL-1, and an increase in IL-4 and IgE is detected [2]. IL-1 is
a major cytokine that leads to the production of other cytokines (IL-2, IL-6,
IL-13, and tumor necrosis factor a), chemotactic factors such as monocyte
chemotactic protein (MCP)-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF), adhesion molecules (intercellular adhesion molecule [ICAM]-1,
vascular adhesion molecule [VCAM]-1), and enzymes (cyclooxgenase, NOsynthase, and phospholipase A2) that are responsible for the production of
inflammation mediators [3]. Increased mucus production and smooth muscle hyperplasia are present [4]. Asthma is usually identified by symptoms such as
shortness of breath, chest tightness, and a decrease in expiratory airflow [5].
Inhaled glucocorticosteroids are indicated for the treatment of persistent
asthma and must be used continuously. Small doses are desired to prevent serious
adverse effects, but with a rise in severity, an increase in dose may be necessary.
For severe cases, a switch to oral glucocorticoids can be indicated. To measure
the effect of inhaled corticosteroids in the treatment of asthma, lung function
tests such as the forced expiratory volume in 1 second, morning and evening
(am/pm) peak expiratory flow, the number of exacerbations and nighttime
awakenings, the measurement of nitric oxide, and the quality of life are performed [69].
Because the treatment of asthma becomes increasingly pronounced and
there is an increased risk for the development of asthma especially in the young
generation, an improvement of inhalation therapy with corticosteroids, the only
anti-inflammatory agent for the treatment of asthma, is essential. Thus,
optimization of the efficacy and safety of inhaled corticosteroids can be achieved
by the pharmacologic properties of the drug, such as an increase in pulmonary selectivity and a decrease in oral bioavailability. Pulmonary selectivity is

Fig. 1. Combination of pharmacokinetics and pharmacodynamics to evaluate the effect of a drug

over time. (From Derendorf H, Meibohm B. Modeling of pharmacokinetic/pharmacodynamic
(PK/PD) relationships: concepts and perspectives. Pharm Res 1999;16(2):17685; with permission.)

inhaled glucocorticosteroids

471

achieved by excellent pulmonary targeting resulting from a prolonged duration of

action in the lung. A negligible oral bioavailability can be achieved by rapid
systemic clearance, a high protein binding, a high receptor binding, a high
volume of distribution, and almost no oral absorption. The pulmonary targeting
can be seen as soon as the corticosteroid is mainly active on the corticosteroid
receptors in the lungs, but not on the other corticosteroid receptors that are found
all over the body.
A comparison of the pharmacologic properties of these drugs can be achieved
by evaluation of the pharmacokinetics and pharmacodynamics of a drug (Fig. 1).
The pharmacokinetics distinguish the concentration of a drug at the site of action
over time, whereas the pharmacodynamics try to relate the drugs concentration
to its clinical effect. To determine the overall effect of a drug over time, a
combination of pharmacokinetics (PK)/pharmacodynamics (PD) data has to be
accomplished. The effect of corticosteroids is their anti-inflammatory activity,
and evaluating the occupancy of the drug at the receptor site over a specific time
period can be explained as the measurement of the response [10].

Currently available inhaled corticosteroids

There are seven different inhaled corticosteroids currently available on the
market (Fig. 2). Triamcinolone acetonide, budesonide, flunisolide, beclomethasone dipropionate, fluticasone propionate, and mometasone furoate have been
used in the clinical setting for a long time. Budesonide and fluticasone propionate
are currently the most frequently prescribed inhaled corticosteroids, whereas
ciclesonide and mometasone furoate are the newer compounds. Ciclesonide is
the only inhaled corticosteroid that was approved only for the European market,
and did not get approved in North America until recently.
The chemical structure of the inhaled corticosteroids is a key to identifying
the pharmacologic and physical properties of the different drugs. Most inhaled
corticosteroids are administered as active compounds with a free hydroxyl group
at C-21.
The free hydroxyl group at position C-21 or the sulfur group in fluticasone
propionate are required for the binding to glucocorticoid receptors. For a better
penetration to the site of action, the hydroxy groups at position C-17 and C-21
can be esterified. The ester formation makes the compound more lipophilic and
therefore it can penetrate through the membranes to reach the cytosolic receptors.
The C-17 monoesters usually have a higher receptor affinity compared with their
parent compound. In beclomethasone dipropionate and ciclesonide, binding to
the receptor is prevented by the existing C-21 ester. These two compounds are
prodrugs that have to be activated by hydrolysis. Pulmonary esterases are responsible for the activation. Ciclesonide gets activated to desisobutyrylciclesonide (des-CIC) [11]. Beclomethasone dipropionate is metabolized in the
lungs to form beclomethasone-17-monopropionate, but it also gets further
transformed to various other active and inactive metabolites [12].

O C

O C

O C

CH3
O
O C CH
3

HO

H
O
O C CH CH CH
22
22
33

HO

CH33
O
O C CH
33

HO

472

CH2 OH

CH2 OH

CH2 OH

Triamcinolone acetonide

Budesonide

O
CH2 O
O

CH 2OH
CH22 CH33

O
O

HO

S CH22 F
O

O C
HO

O
CH3 O

CC
H22 CH33
C CH
CH33

Cl
O

Cl

O
OCC CH22 CH33
O
CH33

Beclomethasone
dipropionate

Fluticasone propionate

Mometasone furoate
O
O
HO

O
O

Ciclesonide

Fig. 2. Structures of the seven inhaled corticosteroids that are available on the market.

hUbner et al

HO

Flunisolide

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473

The fate of inhaled corticosteroids

The fate of an inhaled glucocorticoid relates the safety concerns about the
use of these agents to the route the drugs are taking in the body. The deposition of
the drug in the body compartments depends on the agent and its inhalation
device. Approximately 10% to 60% of the administered inhaled corticosteroid is
deposited in the lungs. The pulmonary deposition percentages of different
inhalers are as follows [1316]:
MDI: 10%15%
Diskus DPI: 14%20%
Diskhaler: 10%15%
MDI with spacer: 15%25%
Turbohaler: 20%30%
HFA-MDI: 60%
In the lungs the agent exerts an effect on the inflamed tissue as soon as it is
dissolved into the pulmonary lining fluid to enter the cells and bind to the
intracellular receptor. In some cases the agent is not active in its native form and
has to become activated first to express an effect (prodrug concept). Over time
the drug gets absorbed and reaches the systemic circulation and adverse effects
can occur.
Additionally, the rest of the drug that did not get deposited in the lung
(40%90%) may reach the systemic circulation after its deposition in the mouth
and pharynx. From there it gets swallowed and reaches the gastrointestinal (GI)
tract. When the drug stays a prolonged time in the intestine, there is an increased
risk for the drug to be absorbed into the systemic circulation. Fortunately, firstpass metabolism in the liver inactivates most of the drug and only a small part
of it is orally bioavailable. The bioavailable fraction can lead to serious adverse
effects as soon as it reaches the corticosteroid receptors of the different body
compartments, but it also diffuses back to the lungs to be absorbed and occupy
the pulmonary anti-inflammatory corticosteroid receptors.

Pharmacodynamics
All inhaled glucocorticoids exert their pharmacologic effects through the
same mechanism: an interaction with intracellular glucocorticoid receptors. The
production of many different cytokines, chemokines, enzymes, and cell adhesion
molecules is inhibited [17].
The reduction of cellular infiltrates and inflammatory proteins leads to better lung function, a decrease in irreversible airway damage and hospitalization,
fewer severe exacerbations, and an improvement in asthma symptoms.
Glucocorticoid receptors are present throughout the body, and the same
mechanism that is responsible for the positive effect in the lungs can cause

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serious adverse effects in other parts of the body. Serious local and systemic
adverse effects are associated with the chronic use of inhaled corticosteroids.
Local adverse effects such as oral candidiasis, hoarseness, and throat infections
are possible. Osteoporosis, growth retardation in pediatric patients, ophthalmologic effects, and adrenal suppression are some of the systemic adverse effects
that can occur during the chronic use of inhaled corticosteroids [18]. Receptor
potency is a pharmacodynamic parameter that is used to evaluate the relationship
between drug concentration and development of an effect.

Receptor potency
Corticosteroid receptors are intracellular. The inhaled corticosteroid has
the ability to diffuse across cell membranes into the cytosol and bind to the
receptor site. Potency of a drug is the ability to produce a pharmacologic
response. The binding ability of inhaled glucocorticoids is expressed by the
receptor affinity compared with dexamethasone. Dexamethasone has a binding
affinity of 100. The higher the binding affinity, the lower the concentrations that
induce an effect. A high potency can be positive because a lower concentration is
needed to exert an effect, but this can also be a safety concern. Of the available
compounds, mometasone furoate has the highest receptor affinity with 2200.
Fluticasone propionate is also potent with a value of 1800. Beclomethasone
monopropionate has a relative potency of 1345, whereas budesonide has an affinity of 935. Flunisolide, triamcinolone acetonide, and beclomethasone dipropionate have lower receptor affinities of 180, 233, and 53, respectively [1923].
Ciclesonide has almost no receptor affinity with a value of 12, whereas its active
principle, des-CIC, is relatively potent with a receptor affinity of 1200 [11].
Knowing the degree of receptor occupancy does not mean that the antiinflammatory effect of the different inhaled corticosteroids can be evaluated by
solemnly looking to the receptor binding. A drug that possesses a higher receptor
binding affinity can show the same degree of pulmonary targeting as a drug with
low receptor affinity. The modulation of pharmacodynamic characteristics of
inhaled corticosteroids cannot induce a better efficacy of the drug in the lungs
[5,24]. However, there are studies available that try to look at the pharmacodynamic properties to develop inhaled corticosteroids that have a better effect in the
lung with lower expression of adverse effects by influencing the transrepression/
transactivation ratio at the receptor site [2527]. Until recently, it was assumed
that all the drugs that bind to the corticosteroid receptors express the same
response as soon as they occupy the receptor. But the present pharmaceutic
development of newer glucocorticoids shows that the drugs seem to induce the
desired effects that are mainly influenced by the transrepression pathway at
the corticosteroid receptor, to a higher extent. They induce the blocking of transcription factors such as activator-protein-1 and nuclear factor (NF)-kB to reduce
the inflammation. But at the same time, the induction of undesired adverse effects
is reduced because the transactivation pathway does not get activated to the same

inhaled glucocorticosteroids

475

extent. Therefore, the synthesis of proteins that again induce the formation of
adverse effects is reduced [28,29]. This observation may be useful to achieve a
better pharmacodynamic profile for inhaled corticosteroids. High lung selectivity
could be achieved for those inhaled corticosteroids that express a higher selectivity for the transrepression pathway. Further studies are necessary to confirm
this observation that may be useful to develop safer inhaled corticosteroids.
Animal models and in vitro models have evaluated the selectivity profile for the
newer glucocorticoids, but for now studies do not show a beneficial clinical effect
that assesses the transrepression and transactivation potencies [30,31].

Pharmacokinetics of Inhaled Glucocorticosteroids

Prodrug design
Beclomethasone dipropionate and ciclesonide are the two agents that can
be distinguished from the other inhaled glucocorticosteroids because they are
prodrugs. These drugs are not active in their native form; they need to be
activated by metabolic reaction. One big advantage of prodrugs can be the
minimization of oropharyngeal adverse effects because the parent compound that
is inhaled through an inhalation device is not pharmacologically active. When
deposited in the oropharynx it does not exert the same effect as the other active
inhaled corticosteroids. Ciclesonide is metabolized to des-CIC through cytosolic
esterases in the airways (Fig. 3) [32,33]. After inhalation it could be shown that
only little activated des-CIC could be recovered from a mouth wash in
comparison to fluticasone propionate [34].
Although it still has to be clarified if other big advantages of prodrugs exist
besides their decreased risk for oropharyngeal adverse effects, it could be
assumed that they have a better pulmonary targeting because of the activation of
the prodrug in the lungs.
However, there is no evidence that the activation specifically occurs in the
lungs. The prodrugs can also be cleaved by esterases outside of the pulmonary
tissue, which could lead to an increased systemic bioavailability of the active

HO
HO

O
CH33
CH
CH
CH22 O C
CC CH
H
CH3
O C
3
HH
O
C
O

HO

CH2 OH
O C
H
O
O C

Ciclesonide

des-Ciclesonide

parent compound

active principle

Fig. 3. Metabolism of ciclesonide parent compound to desisobutyryl-ciclesonide.

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hUbner et al

metabolite. Furthermore, it is necessary for the compounds to be hydrolyzed in

the lungs to exert a favored effect in the lung tissue. An active compound that is
deposited in the lungs can exert an effect without any activation. It must be
assumed that a prodrug gets cleaved by enzymes to its active principle to achieve
the same effect. Further studies are needed to understand its activation properties and possible influence on the pulmonary targeting. Daley-Yates and colleagues [12] showed that 95% of beclomethasone dipropionate that reaches the
lungs gets converted to beclomethasone monopropionate. For ciclesonide more
studies have to be conducted to identify the conversion of the parent compound to
its active principle. It is assumed that almost 100% of ciclesonide is metabolized
to des-CIC.

Oral bioavailability
One parameter that has a high impact on the safety of inhaled corticosteroids
is the bioavailability, because the systemic availability correlates with its rate of
adverse effects. It is necessary to distinguish between oral and pulmonary
bioavailability [19,35]. The pulmonary bioavailability of an inhaled corticosteroid is the rate and extent at which the drug reaches its site of action, and the
systemic bioavailability shows the rate and extent of the drug that reaches the
blood. The sum of pulmonary and oral fraction absorbed represents the systemic
concentration that can lead to systemic adverse effects. A high pulmonary
bioavailability and a low oral bioavailability are desired. Oral bioavailability
depends on the delivery device that is used. Oral bioavailability can be determined by measuring the plasma levels or the amount of drug excreted in urine
over a specific period. Charcoal is used to prevent the absorption of the glucocorticoid from the GI tract. The difference between the drug absorption after
application of inhaled corticosteroids alone and with concomitant charcoal block
reflects oral absorption. Ryrfeldt and colleagues [36] report the oral bioavailability of budesonide to be 11%. In comparison, the study of Thorsson and
colleagues [14] determined that 32% of inhaled budesonide was absorbed without
charcoal and 18% of the dose was absorbed with charcoal. The difference of
14% is similar to the result of 11% that is obtained when oral and intravenous
dosing are compared. Belomethasone-17-monopropionate has a high oral bioavailability of 26% [12,37]. Flunisolide exhibits an oral bioavailability of 7%
[37]. Fluticasone propionate and ciclesonide have negligible oral bioavailabilities
of less than 1% [3840].
There are conflicting studies reported about the oral bioavailability of
mometasone furoate. One single-dose study reported an oral bioavailability of
less than 1% [41]. However, after multiple dose administration a systemic bioavailability of 11% was measured [42].
The oral bioavailability of inhaled corticosteroids has to be small if the
oropharyngeal deposition is high to ensure that enough drug reaches the lungs to
maintain a high pulmonary selectivity.

inhaled glucocorticosteroids

477

Clearance
Systemic clearance (CL) is the parameter that quantifies the elimination of
a drug. After intravenous administration the clearance is calculated by the
following equation:
CL Dose=AUC
It quantifies the volume of body fluid (eg, plasma) that is cleared per time
unit (L/h, mL/min). If there is no saturation of elimination, a clearance is usually
constant and independent of drug concentration. To evaluate the clearance of
an inhaled corticosteroid, its value can be related to the liver blood flow of
approximately 90 L/h [35]. When the liver rapidly metabolizes the compound, it
can be expected that the drug will have a clearance similar to the hepatic blood
flow. The maximum rate of elimination for hepatically metabolized drugs would
be achieved [22]. The clearance for the most inhaled corticosteroids illustrates
that it is similar to the hepatic blood flow. Beclomethasone-17-monopropionate,
budesonide, and fluticasone propionate have a clearance of 120 L/h [12], 84 L/h
[15,36], and 69 L/h [15], respectively. The metabolites of the drugs that are
administered as inactive parent compounds, such as beclomethasone-17monopropionate and des-CIC, have apparent clearance values (CL/F, where F
is the fraction of the parent compound converted to the active metabolite). It is
assumed that the parent compound is completely metabolized to the active
metabolite and that no other metabolism takes place. It is shown that ciclesonide
gets converted to des-CIC in the lungs [33,43]. For des-CIC, the apparent
clearance is reported to be 228 L/h [40,44]. The apparent clearance of des-CIC is
measured after administration of the active principle and does not reflect the real
clearance values after administration of the parent compound. The high clearance
values show that clearance is not only dependent on the hepatic blood flow
but also that extrahepatic clearance has an influence on the elimination of the
drug. New drug developments are working on the development of inhaled
corticosteroids that introduce the extrahepatic clearance to minimize systemic
adverse effects and to increase the pulmonary targeting. Metabolic inactivation of
the corticosteroids in the blood could be a tool to further increase the efficacy
safety profile [5], but it is difficult to design a drug that is efficiently inactivated
in the blood and at the same time has a sufficient stability in the lungs [24].
Because all of the inhaled corticosteroids have a rapid hepatic clearance, there
can be only improvements in drug developments that introduce extrahepatic
clearance properties.
Lung deposition
Lung deposition shows the amount of drug that goes to the lung and therefore explains the quantity that exerts an effect at the site of inflammation. With

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increased lung deposition there is also an increased likelihood that pulmonary

selectivity will be visible. The deposition of an inhaled corticosteroid depends on
several factors: (1) the physical properties of the agent (eg, density, hygroscopy,
charge, velocity), (2) the particle size and shape of the inhaled drug, (3) the
delivery device that is used, and (4) the technique the patient is using. Because
the inflammation of the lung tissue is spread throughout the bronchial tree, the
whole surface of the lungs must be treated [45,46]. The smaller airways can be
easily obstructed, so it is important to get smaller particles to these sites.
For ciclesonide, the deposition is measured as 52% for the hydrofluoroalkane
(HFA) metered-dose inhaler (MDI). However, it is only 16% for fluticasone
propionate with the use of the same inhaler device [34,47]. The difference is
caused by the fact that fluticasone propionate in HFA is a suspension, not a
solution. With the dry powder inhaler, the fluticasone is approximately 10% of
the administered dose [48]. Fig. 4 shows an overview of the lung deposition
of different inhaled corticosteroids that are administered through HFA MDI.
Fluticasone propionate shows the lowest lung deposition of 10% to 20%, whereas
ciclesonide and beclomethasone dipropionate are more than 50% deposited in the
lungs [48]. Low deposition in the lung can be associated with higher drug
deposition in the oropharynx. This parameter is important in how it relates to the
oral bioavailability. It is only important to increase the lung deposition of inhaled
corticosteroids that have a high oral bioavailability. An increase in pulmonary
deposition of these highly bioavailable oral drugs would cause a decrease in drug
that reaches the GI tract to get rapidly absorbed. But for drugs with a low oral
bioavailability, such as fluticasone propionate, mometasone furoate, and
ciclesonide, it is necessary to consider a dose reduction when the lung deposition
is increased; otherwise, more drug can be deposited in the lungs and can become
systemically active through pulmonary absorption.
52

51

Lung deposition in %

50
39

40

28

30

22
20

16

10
0
BDP

FLU

BUD

TAA

FP

CIC

different inhaled corticosteroids

Fig. 4. Lung deposition of different inhaled corticosteroids, that are given by way of HFA-MDI.
BDP, beclomethasone dipropionate; BUD, budesonide (p-HFA-MDI); CIC, ciclesonide (HFA-MDI);
FLU, flunisolide; FP, fluticasone propionate (HFA-MDI); TAA, triamcinolone acetonide. (Data from
Refs. [14,16,35,48,71]).

inhaled glucocorticosteroids

479

Lung deposition is also highly dependent on the patients. The lung anatomy, the breathing pattern, the disease state, the inhalation technique, and
the mucociliary transport are highly variable between patients. Thus, a good
assessment of the patient is the right way to prevent a wrong treatment of the
disease. Studies using gamma scintigraphy were used to evaluate patient training
and the effect of disease. As soon as the patient gets trained in the right usage
of the device, a higher lung deposition can be seen through scintigraphy.
Furthermore, healthy volunteers can inspire the drug more efficiently [49]. The
plasma concentration curves in a moderate asthmatic and a healthy volunteer who
were both using fluticasone propionate through MDI are significantly different.
The levels in healthy subjects are almost twice as high.

Inhaler device
There are different inhalers available on the market. The devices that are
used primarily are pressured MDIs (p-MDIs) and dry powder inhalers (DPI).
Nebulizers are mainly used in children. MDIs are propellant-based and contain
surfactant and lubricants. The newer MDIs use hydrofluoroalkane propellants
(HFA) as their vehicle and the drug is dissolved or suspended in a solution. There
are still some chlorofluorocarbon (CFC)-based MDI suspensions available on the
market, but because of environmental concerns they will be replaced by the HFA
solutions. To use the device, coordination is necessary. The patients must be
assessed for proper technique to ensure they get the desired dose. DPIs are non
propellant-based and contain solid particles. The patient controls the inhalation
although lung function might affect deposition [12,46,5053]. However, they
may contain lactose, which is of concern in patients who have lactose intolerance.
A comparison of budesonide DPI and MDI devices showed the following
deposition: DPI deposition was 38%, with 32% of the budesonide dose deposited
in the lung and 6% in the GI tract, whereas the MDI showed a lung deposition of
15% and a GI tract deposition of 11% (see list above) [14]. As long as the device
is used correctly, the inhaler type is not the main factor that influences lung
deposition [14,54]. The size of the particles and the aerosol vehicle for the MDIs
is of more relevance for the determination of lung deposition.
HFA solutions deliver the drug deep into the lungs; they contain a larger
portion of small particles in the aerosol [55]. Leach and colleagues [56] compared
two beclomethasone formulations: a CFC suspension and an HFA solution. The
HFA-134a showed a much better lung deposition of 55% to 60%, whereas the
CFC preparation was mainly deposited in the oropharynx (90%94%). The HFA
solution contains much smaller particles (12 mm versus 25 mm) because the
drug gets dissolved in the solution and the distribution throughout the lungs is
more diffuse than with the CFC suspension. The change to the HFA-based
formulations was not easy; the CFC suspensions were already established in the
market and the lower pulmonary deposition of the CFC-MDI resulted in many
challenges because there is no dose equivalence between CFC and HFA products.

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The invention of the newer HFA-134a showed some advantages compared

with the older CFC suspensions. As soon as the corticosteroid is dissolved in the
HFA solution it has a much higher chance to reach the pulmonary receptor sites.
Thus pulmonary targeting could be improved by changing the propellant. A main
advantage of DPIs is that patients control the intake of the drug by their own
inhalation technique. When patients are compliant with the use of their inhaler
device, the risk for adverse effects can be decreased because of a higher pulmonary selectivity.
Particle size
The particle size of the dry powder or aerosol droplets is most effective in a
range of 1 to 5 mm median aerodynamic diameter [57]. Particles larger than 5 mm
are deposited in the mouth and trachea, where they may cause local adverse
effects. The larger particles that are of low density and porous can still pass the
trachea and be deposited in bronchi and bronchioles. If the particles are too small,
they pass into the lungs but they will be exhaled immediately. However, ultrafine
particles (b 0.3 mm) may be of interest because they can penetrate into small
airways that have an internal diameter of less than 2 mm.
Protein binding
Protein binding is highly relevant because only the unbound free drug can
exert an effect at the receptor side. As long as the corticosteroid is bound to a
protein, it is unable to bind to any corticosteroid receptor. Albumin is the major
protein involved in protein binding with inhaled corticosteroids. Protein binding
is seen as a storage form of the drug because it is reversible and a rapid equilibrium is established. High protein binding can be advantageous because the
protein binding decreases the free unbound fraction in the systemic circulation
and therefore the risk for a systemic adverse effect is also decreased. Protein
binding has been reported to be 80% for flunisolide, 87% for beclomethasone
dipropionate, 88% for budesonide, 71% for triamcinolone acetonide, and 90% for
fluticasone propionate [19,22,36,58]. Fig. 5 shows the protein binding of
ciclesonide and its active compound to be 99% [23]. With an increase in protein
binding, the systemic bioavailability of the drug is assumed to be decreased, as
seen with ciclesonide and mometasone furoate. This decrease can lead to a better
risk/benefit ratio because the risk for systemic adverse effects is decreased.
Protein binding can have an effect on the clearance of some drugs, but
that is not the case for inhaled corticosteroids. Inhaled corticosteroids are high
extraction drugs, which means they have a high metabolic activity and a high
hepatic clearance, and therefore the protein binding does not limit clearance and
a change in protein binding does not alter the clearance.
Newer compounds show an improvement in protein binding. The drugs
become more and more bound to the plasma proteins and it is assumed that less

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inhaled glucocorticosteroids
120

Protein binding (%)

99
100

87

99

90

88
80

80

71

60
40
20
0
BDP

FLU

BUD

TAA

FP

CIC

des-CIC

Inhaled Corticosteroids
Fig. 5. Comparison of the protein binding of inhaled corticosteroids. BDP, beclomethasone
diproprionate; FLU, flunisolide; BUD, budesonide; TAA, triamcinolone acetonide; FP fluticasone
propionate; CIC, ciclesonide (Data from Refs. [22,23,36,58]).

free drug concentration will lead to fewer systemic adverse effects. The increased
protein binding seems to be another property that can influence the development
of safer inhaled corticosteroids.

Volume of distribution
The volume of distribution is a pharmacokinetic parameter that illustrates
the distribution of a drug in the body [35]. A highly lipophilic drug shows a high
distribution because the drug can pass the lipophilic membranes in a high extent
and mainly goes to the tissue compartments. A drug that has a high lipophilicity
enters the tissues to a high extent, but the retention time of the drug in the tissue is
dependent on the equilibrium that develops between the tissue and the systemic
circulation. Volume of distribution is therefore calculated by the ratio of the
fraction unbound in plasma (fu) and in the tissue compartment (fuT) and the
volume of the plasma. A drug can be stored in the tissue for a long time if
the equilibrium is low [35,55]. The higher the tissue binding compared with the
plasma protein binding, the higher the volume of distribution. This higher volume
of distribution leads to less drug that is available in the systemic circulation and
an increase in the half-life of the drug. The increase in pulmonary residence time
is a desired feature of inhaled corticosteroids. However, an increase in tissue
binding is most likely to result in decreased pulmonary activity of inhaled
corticosteroids because the drug that is bound to the tissue is not available to exert
an effect at the pulmonary receptor site.
Beclomethasone-17-monopropionate has an apparent volume of distribution
(Vd/F) of more than 400 L, the active principle of ciclesonide is even more
distributed to the tissue with a Vd/F of almost 900 L, and budesonide and
fluticasone propionate have volumes of distribution of 183 L and 282 to 318 L,

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hUbner et al

respectively [14,49,59]. Currently, there are more lipophilic drugs in development

that have a high affinity to plasma proteins and a high tissue binding capacity to
lower the free fraction in plasma and proteins (fu and fuT). But the volume of
distribution cannot increase significantly because the ratio between the two
unbound fractions will remain the same. Volume of distribution does not seem to
be an important parameter that could be used for a desired increase in pulmonary
selectivity. But from a safety perspective, the high volume of distribution has
been shown to lead to low free drug concentrations in the systemic circulation
and this can furthermore decrease the risk for the development of serious
systemic adverse effects.
Half-life
The systemic elimination half-life is an important parameter that expresses
the time it takes to reduce the concentration of a drug in the systemic circulation
by half. It is calculated from systemic clearance and volume of distribution
[19,35].
t1=2 0:693  Vd =CL; where t1=2 is the half -lif e and Vd is the
volume of distribution
From a safety prospective, elimination of the drug from the systemic
circulation in a short time is desired because the drug shows a high clearance
property. However, high volume of distribution leads to low drug concentration
in the systemic circulation. As soon as clearance is approximately the same in the
different inhaled corticosteroids, a higher elimination half-life can most likely be
correlated to an increase in volume of distribution. Thus, drugs with a high
elimination half-life do not influence safety, as long as the t1/2 is caused by
extensive tissue binding and not a decrease in the clearance of a drug. Inhaled
corticosteroids have a rapid clearance. The rapid clearance is desired to minimize
systemic exposure of the drug to the body and therefore decrease the risk for
adverse effects. Fluticasone propionate has the longest elimination halflife, with
7.8 hours [15] reported for intravenous administration and more than 14 hours for
inhaled administration. It is followed by mometasone furoate with a half-life of
5.8 hours [58]. Budesonide has a fast first-pass metabolism and a high clearance
with a half-life of 2.8 hours [36], whereas flunisolide has an elimination half-life
of 1.6 hours [21]. Beclomethasone dipropionate gets rapidly metabolized and has
a half-life is only 0.5 hours, whereas the metabolite beclomethasone-17monopropionate was reported to have a half-life of 2.7 hours [12]. Ciclesonide
has a reported half-life of 0.7 hours because it also gets rapidly metabolized.
Des-CIC was reported to have a half-life of approximately 3.5 hours [23]. In
conclusion, the elimination half-life is a parameter that does not have any influence because it reflects the relationship between systemic clearance and
volume of distribution.

inhaled glucocorticosteroids

483

Pulmonary residence time

An optimum pulmonary residence time illustrates a high degree of pulmonary selectivity. It is beneficial because the drug is trapped in the lungs to exert
the positive anti-inflammatory effect and at the same time the absorption of the
drug is delayed. The pulmonary membranes are thin and leaky [5]. They consist
of several pores, and there is a large blood flow through the lungs to ensure an
ample gas exchange. In general, drugs that are dissolved in a solution are
absorbed quickly [24]. Inhaled corticosteroids are inhaled as liquid suspension
or in dry powder formulations. A drug that enters the lungs with a low lipophilicity dissolves in a short time into the pulmonary lining fluid. From there it
will diffuse to the receptor site to exert an effect, but it does not stay in the
inflamed tissue for a long time because rapid absorption into the systemic
circulation occurs. The dissolution rate of particles is an important parameter
that influences the pulmonary residence time. Another important pathophysiologic parameter is the mucociliary clearance of the drug in the lungs. A drug
that does not get dissolved within a specific time can be removed from the upper
part of the lungs by mucociliary transport. This fraction of the drug is swallowed
and does not exert a pulmonary effect. The development of strategies to ensure
an optimal drug-release rate is in evaluation. To prolong the pulmonary residence time, an inhaled corticosteroid has to provide an optimal dissolution rate
or the formulation of the drug has to have slow-release characteristics [5,24].
Some newer developments use liposomes [6063] or microspheres [64] to adjust an optimum drug-release rate. Another option is the use of drug coatings
(eg, nanothin coatings of biodegradable polymers, trehalose-based coatings)
to guarantee a slower release of the drug in the lungs [65]. For budesonide and
des-CIC, a biologic system is used to prevent the absorption into the systemic circulation.
Corticosteroids can be esterified intracellularly by fatty acids [6670]. This
fatty acid conjugation has been shown for budesonide and des-CIC. The
mechanism that is underlying fatty acid conjugation is an intracellular enzymatic
reaction between a fatty acid and the hydroxyl group at position 21 of the
steroids. At least five different fatty acids seem to be involved. Radiolabeled
ciclesonide was used to evaluate the ability to bind to the airway tissue and create
a slow-release reservoir [43,66]. Slices of human lungs were precisely cut and,
after incubation for 2, 6, and 24 hours with radiolabeled ciclesonide, the radioactivity of the tissue was quantified, revealing the appearance of lipid conjugates.
The benefit of the fatty acid conjugation is the creation of a slow-release depot.
The effect in the lung can be prolonged and systemic adverse effects can be
decreased. It still must be evaluated, if this positive lipid conjugation is the
rationale for once-daily dosing of these steroids [48]. Budesonide [66,68] and
des-CIC [33,43] have been shown to undergo this mechanism. They provide a
local depot and form in vivo reversible fatty acid ester conjugates in the lungs.
However, the clinical efficacy of this ester trapping has to be evaluated to develop
and modify corticosteroids with an optimal pulmonary residence time.

484

hUbner et al

The encapsulation of glucocorticoids in liposomes have been studied lately

in animal and in vitro models [60,61,63]. One study showed that a weekly
therapy with budesonide encapsulated in stealth liposomes was as effective as
daily budesonide therapy in the reduction of inflammation markers in the lungs
[63]. A disadvantage of liposomal formulations is their potential instability
and studies are necessary to develop a product that can be marketed, but the
possibility of decreased toxicity caused by an increase in pulmonary residence
time can be seen. In addition, the once-weekly dosing of the encapsulated
glucocorticoids could offer an effective alternative to the daily asthma therapy
because it could lead to a better patient compliance.

Summary
A comparison of the pharmacodynamics and pharmacokinetics of inhaled
corticosteroids is necessary for their assessment. A good knowledge of these two
aspects allows the optimization of efficacy and safety.
The currently available inhaled corticosteroids already show some of the
desired PK/PD parameters. The local adverse effects are decreased as soon as
the inhaled corticosteroid is administered as an inactive prodrug or shows a better lung deposition. HFA-MDI beclomethasone dipropionate (BDP) and ciclesonide are two agents that illustrate this. Low oral bioavailability, rapid systemic
clearance, and high plasma protein binding can minimize systemic adverse effects.
Mometasone furoate, ciclesonide, and fluticasone propionate possess those characteristics. The pulmonary efficacy is maximized by high lung deposition and long
pulmonary residence times. This effect can be achieved by slow dissolution in the
lungs, as is the case for fluticasone propionate or lipid conjugation and has been
shown for budesonide and ciclesonide. Furthermore, the lung deposition depends
on the inhalation device, the particle size, and the inhalation technique. Therefore,
improvement in the design of MDIs, DPIs, and nebulizers, and the development of
more effective drug particles will lead to an optimized pulmonary targeting.
Much progress has been made in the treatment of asthma. The available inhaled corticosteroids show a high safety profile and a good pulmonary selectivity.
Development of newer compounds showed that improvement is possible as
the result of a complete understanding of the PK/PD concepts. However,
the introduction of further improved formulations with a better efficacy/safety
profile will be difficult and protracted because the existing drugs are already
highly efficient.

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