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Respiratory Medicine (2005) 99, 836–849

KEYWORDInhaled cooids;BudesonidDelivery dAsthma;COPD

0954-6111/$ - sdoi:10.1016/j.r

�Correspondifax: +46 46 337

E-mail addr(L. Thorsson).

Factors guiding the choice of delivery device forinhaled corticosteroids in the long-termmanagement of stable asthma and COPD:Focus on budesonide

Lars Thorssona,�, David Gellerb

aAstraZeneca R&D, Experimental Medicine, 221 87 Lund, SwedenbThe Nemours Children’s Clinic, Orlando, FL, USA

Received 24 September 2004

Srticoster-

e;evices;

ee front matter & 2005med.2005.02.012

ng author. Tel.: +46 46192.ess: lars.thorsson@astra

Summary Inhaled corticosteroids (ICSs) have become the mainstay of chroniccontroller therapy to treat airways inflammation in asthma and to reduceexacerbations in chronic obstructive pulmonary disease. An array of ICSs are nowavailable that are aerosolized by a range of delivery systems. Such devices includepressurized (or propellant) metered-dose inhalers (pMDIs), pMDIs plus valved holdingchambers or spacers, breath-actuated inhalers, and nebulizers. More recently, dry-powder inhalers (DPIs) were developed to help overcome problems of hand–breathcoordination associated with pMDIs.

The clinical benefit of ICSs therapy is determined by a complex interplay betweenthe nature and severity of the disease, the type of drug and its formulation, andcharacteristics of the delivery device together with the patient’s ability to use thedevice correctly.

The ICSs budesonide is available by pMDI, DPI, and nebulizer—allowing thephysician to select the best device for each individual patient. Indeed, theavailability of budesonide in three different delivery systems allows versatility forthe prescribing physician and provides continuity of drug therapy for youngerpatients who may remain on the same ICSs as they mature.& 2005 Elsevier Ltd. All rights reserved.

Elsevier Ltd. All rights reserv

336 337;

zeneca.com

Introduction

Asthma and chronic obstructive pulmonary disease(COPD) are common respiratory conditions that havea major impact on society in terms of morbidity,mortality, and costs. They are characterized by

ed.

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Inhaled corticosteroids in the asthma and COPD 837

chronic inflammation of the airways associated withvariable airflow limitation. The worldwide preva-lence of both diseases is increasing, together withthe concomitant implications for the health of thepopulation and the cost to society.1,2

Anti-inflammatory and bronchodilator medicationsfor asthma and COPD are delivered by inhalation tothe affected sites—the airways and lungs. Topicalapplication of these drugs to the lung maximizesefficacy and minimizes potential side effects. Inhaledcorticosteroids (ICSs) are more effective than cro-mones or leukotriene modifiers in the control ofasthma and are now regarded as the preferredtherapy for patients with mild, moderate, or severepersistent asthma.3,4 In addition, a variety of deliverysystems are used to target ICSs to the airways,including pressurized (or propellant) metered-doseinhalers (pMDIs), pMDIs plus valved holding chambersor spacers, breath-actuated MDIs, dry-powder inha-lers (DPIs), and nebulizers.

The primary objective of ICSs therapy in patientswith asthma or COPD is to deliver sufficiently highconcentrations of the drug to the bronchialmucosa, while minimizing the amount of drugreaching the systemic circulation and thus reducingthe potential for adverse systemic and local sideeffects. Many factors influence the distribution ofan aerosolized drug throughout the tracheobron-chial tract and its subsequent metabolic fate andtherapeutic effects. These factors can be dividedinto three major categories (Table 1):

�

drug- and formulation-related factors; � device-related variables; � patient- and disease-related factors.

Table 1 Factors affecting the clinical outcome of thera

Drug- and formulation-relatedfactors

Device-related fact

Potency and airway selectivity ofthe drug

Lung deposition pro

Pharmacokinetic profile of the drug Aerosol particle sizPulmonary and oral

bioavailabilityEase of use

Local retention Dosage accuracy

Particle size Extrathoracic depofor local and system

Choice of propellant (pMDIs) Driving gas flow (neIrritancy of additives Choice of face mask

(nebulizers)Viscosity and surface tension ofnebulization solution

Abbreviation: pMDIs, pressurized metered-dose inhalers.

to address the different clinical circumstances and

A range of delivery devices have been developed

patient types receiving ICSs treatment. The clinicalbenefit of therapy is affected by the nature andextent of the patient’s disease, the drug andformulation, the characteristics of the device,and the patient’s ability to use the device correctly.An understanding of these factors is necessarywhen considering the most appropriate treatmentoption. The aim of this review is to examine thekey factors influencing the relative clinical efficacyand safety of the different inhalation systems forthe delivery of corticosteroids to patients withasthma and COPD, and thus help guide selection ofthe most appropriate delivery device for theindividual patient.

Throughout this review, the corticosteroid, bu-desonide, has been used as an example to explainthe impact of these factors using various deliverydevices. Budesonide has been selected for this rolein view of the extensive evidence demonstrating itsefficacy in the treatment of persistent asthmaacross all age groups.5

Delivery options for inhaledcorticosteroids

pMDIs consist of a pressurized aerosol canister thatcontains the medication either dissolved or sus-pended in liquefied gas propellant(s), together withsurfactants and other excipients, such as preserva-tives and flavourings. A metering system controlsthe volume of drug mixture that is released when

py with an ICS.

ors Patient- and disease-relatedfactors

perties Inspiratory flow rate

e Upper airway anatomyLower airway obstruction

Ability to use device effectively(competence)

sition (relevantic side effects)

Patient preference

bulizers) Patient adherenceor mouthpiece Handling and maintenance of the

deviceBreathing pattern (nebulizers)

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L. Thorsson, D. Geller838

the actuator is pressed. The propellant that formsthe aerosol has historically been a chlorofluorocar-bon (CFC), but due to environmental concerns,they are gradually being replaced with hydrofluor-oalkanes (HFAs). Most HFA formulations have agentler plume (slower particle velocity) and thesolution HFA formulations have reduced particlesize that can dramatically influence lung depositionvs. a CFC suspension.6 About 80–90% of the ICSsdose from a CFC-pMDI is deposited in the orophar-ynx where it can cause local side effects. Further-more, a major limitation of pMDIs is that theyrequire coordination of actuation and inhalation.Effective patient instruction, including practicewith a placebo device, is therefore essential.Patients may also have difficulty using the mouth-piece of the actuator, and the cold temperature ofthe aerosol when it hits the back of the throat maycause the user to interrupt inhalation (known as the’’

cold Freons effect’’).A host of add-on devices for pMDIs have been

designed to overcome these limitations. Spacersand valved holding chambers are designed to reducehigh oropharyngeal drug deposition and eliminatethe cold Freons effect. Valved holding chamberscan also reduce drug loss caused by poor hand–

breath coordination. Breath-actuated or flow-trig-gered pMDIs were developed to overcome the needfor hand–breath coordination. However, thesedevices still require a proper technique when usedwith a slow inhalation and a breath-hold, which maybe difficult for some patients, particularly youngchildren. Therefore, valved holding chambers withface masks are available for infants and youngchildren and are used with tidal breathing.

DPIs offer an alternative response to the diffi-culties associated with pMDIs, and are actuated anddriven by inspiratory flow. These devices create theaerosol by passing air from the inspiratory effortthrough medication formulated as a dry powder.The active ingredient is in the form of micronizeddrug particles that can be mixed with largerglucose or lactose particles, or bound into looseaggregates. Micronized particles tend to adherestrongly to each other and to most surfaces, anddisaggregation must occur for the drug to bedelivered effectively. Disaggregation occurs duringinhalation when the powder is broken up into itsconstituent particles by turbulent airflow and/ormechanical devices, such as screens or spinningsurfaces. One type of DPI is TurbuhalerTM, which isroutinely used for the delivery of asthma medica-tion. TurbuhalerTM has a built-in resistance in theform of a spiral-shaped air passage that promotesthe separation of the dry-powder microaggregatesof drug into particles of respirable size before they

leave the inhaler. However, with this formulation itis important to educate the patient that the aerosolhas no flavour, otherwise the patient may be unsurewhether a dose was delivered by the device.

Nebulizers have been available in one form oranother for over a century. They produce a fine mistof droplets that contains the active drug. Nebuli-zers are a practical means of administering inhaledmedications to very young children and patientswho are unable to use other inhaler devices. Theyare also used in preventive and emergency con-texts. There are two classic types of nebulizers,which are classified according to how they producethe droplets. Jet nebulizers use a source ofcompressed air forced through a small orifice,forming an air jet that transforms a liquid intoprimary aerosol droplets. The larger particlesimpact on internal baffles and are recirculated,while the smaller particles exit the nebulizer andare available for inhalation. Ultrasonic nebulizersproduce the droplets by mechanical vibration of apiezoelectric plate, creating a geyser or fountaineffect from which particles of the liquid arecreated. The former type is less complex, cheaperand therefore more commonly used. The drug iscontained in an aqueous solution or as a suspension(Pulmicort Respuless [budesonide]) in which smallparticles are suspended in the fluid. The mist isthen inhaled via a mouthpiece or a face mask. Newtypes of nebulizers, such as those that use vibratingporous membrane technology, are under develop-ment and may be useful for both solutions andcertain suspensions.

Preclinical and clinical pharmacologiccomparison of the delivery options forinhaled budesonide

In vitro characteristics of the device

Aerosol particle/droplet size is one of the mostimportant factors determining the deposition ofICSs in the airways.7,8 The portion of an aerosolthat has the highest probability of bypassing theupper airway and depositing in the lung measurebetween 1 and 5 mm.9 Particles larger than this aregenerally deposit in the oropharyngeal region andare swallowed, while submicronic particles do notcarry much drug and may be exhaled beforedeposition takes place. Smaller particles tend todeposit more peripherally in the lung than coarserparticles, which may lead to a different clinicalresponse.10 Consequently, differences in particlesize of the aerosol emitted from inhalation devices

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FluticasoneDiskhaler®(61, 91, 122 l/min)

BudesonideTurbuhaler® (40, 60, 80 l/min)

BeclomethasoneChiesi inhaler(19, 29, 38 l/min)

BeclomethasoneDiskhaler® (79, 118, 158 l/min)

Inhaled corticosteroids in the asthma and COPD 839

may account for some of the variability intherapeutic efficacy and safety of the various ICSs.Measurement of particle size, therefore, has animportant role in guiding product development andin quality control of the marketed product.

The distribution of aerosol particle/droplet sizecan be expressed in terms of either:

60

�

al d

ose)

50

the mass median aerodynamic diameter(MMAD)—the droplet size at which half of themass of the aerosol is contained in smallerdroplets and half in larger droplets;

in

�

Inspiratory force

Fin

e pa

rtic

le d

ose

(% o

f nom

Weak Moderate Strong0

10

20

30

40

Figure 1 The proportion of the nominal dose ofbudesonide, beclomethasone dipropionate, or flutica-sone delivered as fine particles (diameter o5mm) fromfour different DPIs at flow rates corresponding to weak,moderate, and strong inspiratory forces in an in vitromodel.11

the fine particle fraction—the percentage ofparticles that are o5 mm in diameter.

These measures have been used for comparisonsof the in vitro performance of different inhalerdevice and drug combinations. In general, thehigher the fine particle fraction, the higher theproportion of the emitted dose that is likely toreach the lung. Fine particle fraction (and conse-quently fine particle dose) can be assessed bydrawing aerosols through an Andersen multi-stagesampler (an impactor device fitted with a series offilters that collect progressively smaller particles).The inhaler and impactor are connected via an inletthroat. These laboratory assessments of fine parti-cle dose have been shown to correlate well withlung deposition in humans if the traditional inletthroat is replaced with an anatomically accuratereplica or cast of the human throat.7 Interestingly,the choice of inlet throat has a significant effect onthe fine particle dose recovered from a pMDI (50%difference in fine particle fraction between throats)but considerably less influence on that recoveredfrom a DPI (15% difference).11 This suggests that inhumans, the interaction between the throat and theaerosol cloud is greater for an aerosol generated bya pMDI than for one generated via a DPI.7

Using the anatomically correct throat methoddescribed above, Olsson11 has shown that the invitro fine particle dose of budesonide (expressed asa per cent of the nominal dose) via TurbuhalerTM

DPI is approximately twice that achieved via apMDI. Conversely, for fluticasone propionate (here-after referred to as fluticasone) the oppositeappears to be true—i.e. the fine particle dosedelivered via pMDI is about twice that via theDiskhalers DPI.11 This illustrates the point that allinhaled formulations have unique properties;hence, no general conclusions should be made forDPIs, pMDIs, or nebulizers. Figure 1 shows an invitro comparison (using similar methodology to thatdescribed above) of the proportion of the nominaldose of budesonide, beclomethasone dipropionate,or fluticasone delivered as fine drug particles

(o5 mm) from four different DPIs at flow ratescorresponding to weak, moderate, and stronginspiratory force.11 Comparable degrees of inspira-tory force, rather than identical flow rates, wereused since different DPIs offer different resistanceto inspiratory flow. These data show that thebudesonide TurbuhalerTM device consistently pro-duced a higher proportion of respirable particlesthan the other devices (even when the inspiratoryforce was relatively weak), indicating that thisdevice could be considered for patients withrelatively low inspiratory abilities.

Pulmonary/extrapulmonary deposition andinhalation characteristics

The clinical efficacy and safety of ICSs in asthmaand COPD is dependent upon maximizing theproportion of the dose that is delivered to thelungs and airways, while minimizing systemicexposure to the drug. While in vitro assessmentsof fine particle mass do provide some predictive

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L. Thorsson, D. Geller840

information on the behaviour of an aerosolized drugwithin the tracheobronchial tree, a number ofother factors (plume geometry [pMDIs], particleinertia, breathing pattern, inhalation flow, anddisease-related changes in airway geometry andflow) also influence pulmonary disposition. There-fore, in vivo deposition studies are also needed tosupport the in vitro findings.8

There are two main methods used to measureaerosol deposition in the lungs. First, g-scintigraphyis performed by radiolabelling the drug with asubstance like 99m-technetium, and scanning thesubject after inhalation of the drug. This techniquehas the advantage of being able to quantify theproportion of aerosol inhaled by the patient, aswell as regional distribution in the upper airwayand lungs. Second, since most of the ICSs depositedin the lower airways will be absorbed into thebloodstream, pharmacokinetic techniques are usedto measure lung deposition. This technique canassess the total amount of ICSs that interacts withthe airway epithelium and is absorbed systemically,but will miss the small portion that may beexpectorated or swallowed after mucociliary clear-ance, and cannot tell us about regional distribu-tion. Therefore, g-scintigraphy and pharmaco-kinetic studies are complementary, and have both

Table 2 Fine particle mass (presented as percentage ofavailable devices for delivery of ICSs (deposition data for

Reference Device Lung de

Per centnominal

BudesonideDahlstrom et al.13 PARI Inhalierboys 14

PARI LC Jet Pluss 14Maxin MA-2s 14

Borgstrom12 andThorsson et al.14

pMDI (no spacer) 15

Thorsson andEdsbacker15

pMDI plus spacer 36

34Borgstrom,12 Thorssonet al.,14,16 Borgstromet al.,17 and Agertoftand Pedersen18

TurbuhalerTM 28–32

Fluticasone propionateThorsson et al.16 PMDI 20Thorsson et al.16 andAgertoft andPedersen18

Diskuss 8–12

Abbreviation: pMDI, pressurized metered-dose inhaler.

been used for budesonide and other ICSs deliveredby nebulizers, MDIs and DPIs.

Deposition studies have shown significant differ-ences between devices with respect to pulmonarydeposition of corticosteroids, with values rangingfrom approximately 5% to over 50% (ex-actuatoror delivered dose, respectively) for currentlyavailable corticosteroid pMDIs and DPI systems(Table 2).6,12 For example, Thorsson et al.14

reported that lung deposition of budesonide inhealthy volunteers was approximately twice as highwhen the drug was delivered via TurbuhalerTM thanvia a pMDI (32% and 15% of the metered dose,respectively). Moreover, TurbuhalerTM depositedless drug in the mouth than pMDI, resulting in amore beneficial ratio of pulmonary to totalsystemic bioavailability (Fig. 2). In this study,deposition was calculated by two methods: fromsystemic availability (corrected for an assumed oralbioavailability of 13%) and using the charcoal blocktechnique (in which activated charcoal suspensionis used to adsorb swallowed drug, preventing itssystemic absorption); similar results were obtainedwith each of the techniques (Table 2). The doublingin pulmonary deposition of budesonide with Turbu-halerTM compared with pMDI14 is consistent with invitro fine particle results obtained using an Ander-

dose) and estimated lung deposition of the currentlyhealthy volunteers).

position Systemic availability(per cent of nominaldose)

ofdose

Per cent of doseto subject

36 1758 1559 17

21–26

36

3559 33–38

31 2117 13

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Figure 3 Lung deposition of radiolabelled budesonide,measured by g-scintigraphy, following administration ofbudesonide via (a) pMDI, (b) pMDI plus Nebuhaler, and (c)TurbuhalerTM.19

40

35

30

25

20

15

10

5

0 Nor

mal

ised

to lu

ng d

ose

(%)

Nor

mal

ised

to m

eter

ed d

ose

(%)

Turbuhaler PMDI Turbuhaler PMDI0

20406090

100120140160180

Gastrointestinal contribution

Gastrointestinal contributionWith mouth rinsing

Lung availability

Figure 2 Systemic availability of budesonide followingsingle-dose administration via TurbuhalerTM and pMDI tohealthy volunteers, expressed as (a) per cent of thenominal dose and (b) per cent of the lung dose.14

Inhaled corticosteroids in the asthma and COPD 841

sen sampler fitted with an anatomical throatmodel.11 This finding suggests that in the case ofbudesonide, this in vitro technique may be a usefulpredictor of relative lung deposition.

There are significant differences between thedeposition characteristics of various DPIs as well.For example, Thorsson et al.16 evaluated thepharmacokinetics of budesonide delivered by Tur-buhaler vs. fluticasone delivered by a pMDI and byDiskus DPI in 13 healthy adult volunteers and eightadults with asthma. The delivery to the lung withthe Turbuhaler was almost twice that of the pMDIand almost three times that of the Diskus (34%,20%, and 13%, respectively). Similarly, in a group ofchildren ages 8–14 years, the lung dose ofbudesonide via Turbuhaler was almost four timesthat of the fluticasone Diskus (30.8% vs. 8.00%).18

One cannot comment on the superiority of a drug-device combination based on lung deposition alone,but the effectiveness of topical therapy obviouslydepends on the medication being delivered to theairways target effectively.

The efficiency of a pMDI at delivering drug to thelung can be improved by using the pMDI inconjunction with a large-volume spacer or valvedholding chamber. In healthy volunteers, lungdeposition of budesonide from a pMDI plus Neb-uhalers (not available in the US) was estimatedusing pharmacokinetic methods to be 36% of themetered dose.15 Similarly, in patients with asthma,the mean lung deposition, measured by g-scinti-graphy, was 38% from pMDI plus Nebuhalers

compared with 26% from TurbuhalerTM, and 12%from a pMDI alone (Fig. 3).19 Another study showedthat the efficacy of a pMDI plus Nebuhalers usedunder ideal circumstances could indeed match the

clinical efficacy of budesonide TurbuhalerTM.20

However, the high lung deposition of budesonidereported in these studies with a pMDI plusNebuhalers does not appear to translate intosuperior clinical efficacy compared with Turbuha-lerTM in routine practice (as explained in thesubsequent sections).21 This may be related toproblems in using pMDIs plus spacers correctly or topoor adherence in routine clinical practice, asopposed to the highly controlled environment inwhich clinical trials are performed.15,22 Alterna-tively, subjects may have already been on theplateau of the dose–response curve, so using amore efficient device may not have improvedclinical outcome.

While some of the newer HFA-propellant pMDIsare formulated with the drug in suspension, mosthave the drug in solution, e.g. beclomethasonepropionate, flunisolide, and ciclesonide. Beclo-methasone has an MMAD close to 1 mm and an ex-actuator deposition efficiency of about 50% inadults6 and greater than 30% in children.23 Thefluticasone HFA formulation has a larger particlesize to emulate the CFC preparation.

In children or adults who are unable to use a pMDIor DPI correctly, a jet nebulizer can be used todeliver therapeutic levels of any corticosteroidavailable as a nebulizing suspension (beclometha-sone and budesonide) to the lungs. Dahlstromet al.13 assessed lung deposition of budesonide bypharmacokinetic methods in adult volunteers fromthree different jet nebulizer systems—the PARIInhalierboys, PARI LC Jet Pluss, and Maxin MA-2s.The MMAD for the Inhalierboys, Jet Pluss, and MA-2s systems were 7, 5, and 3 mm, respectively.Relative to the nominal budesonide dose, lung

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deposition was similar via the three nebulizerstested, ranging from 14% to 16%, despite thedifferences in particle size distributions. Thisemphasizes the fact that particle size is only oneof the important variables in the assessment ofaerosol delivery system performance. In this study,even though the PARI Inhalierboys produced largerparticles that are less likely to deposit in the lungs,it had a higher total output of drug than the othernebulizers which compensated for the particle sizeproblem. The pharmacokinetics of budesonidenebulizing suspension have also been studied inasthmatic preschool children aged 3–6 years, usinga PARI LC PLUS with a mouthpiece. Lung depositionas a per cent of inhaled dose was 18%, and thesystemic bioavailability was 6%, which is about halfthat of adults.24 This indicates that the lower totallung dose in children is due to the increasedfraction of the drug filtered out by the oropharynx(which does not add significantly to the systemicload) indicating the same doses can safely be usedin children as adults.

Ultrasonic nebulizers are not well suited forsuspensions, as demonstrated in several stu-dies.25–27 For example, in one study the medianinhaled mass of budesonide was approximatelythree-fold lower with an ultrasonic nebulizercompared with a jet nebulizer (10% of the nominaldose vs. 31%).28 For this reason, ultrasonic nebuli-zers are not recommended for use with budesonidenebulizing suspension.

Lung deposition and inhaled mass of nebulizercorticosteroids are also significantly influenced bythe choice of patient–device interface, with use ofa mouthpiece being shown to double lung deposi-tion compared with use of a face mask.29 Forexample, one study of 158 children with asthma(ages 5–15 years) reported a mean inhaled mass of5–7% of the nominal dose when budesonide wasadministered at a constant output using a jetnebulizer fitted with a unsealed face mask,compared with 9–12% when the same device wasused at the same output but using a mouthpiece.29

Based on these data, the authors recommendedthat the use of non-sealing face masks with jetnebulizers should be avoided where possible. Meaninhaled mass could be further increased by switch-ing the jet nebulizer from constant output to thebreath-synchronized mode (an increase of up to17–22% when used in conjunction with a mouth-piece).29 Despite the higher inhaled mass notedwith the mouthpiece vs. the mask, a large clinicaltrial showed improvement in asthma symptomscores of similar magnitude between the twopatient–device interfaces.30 In this study of infantsand children aged 6 months to 8 years, the mask

was used more in the younger children (mean 36.4months) and the mouthpiece in older children(mean 70.0 months). The similar clinical effectbetween groups may be due to the smaller lungsand therefore a lower lung-dose requirement in theyounger children.

Relationship between pulmonary deposition andtherapeutic effectThe relationship between pulmonary deposition ofinhaled b2-agonists and therapeutic effect is nowwell established8,31,32 since the immediate effectsof these agents on the airways are relatively easy tomeasure.8 As the pulmonary dose–response curvefor the b2-agonists is sigmoidal (i.e. an initial slopefollowed by a plateau), increasing the dosedeposited in the lung will elicit an increasedtherapeutic effect only if the initial dose was onthe rising slope of the dose–response curve. Thelack of measurable acute effects with ICSs makes itimpossible to perform similar single-dose studieswith these agents, although there are now anumber of long-term studies suggesting that therelationship also holds true for corticoster-oids.8,33,34 Therefore, for patients whose symptomsare not currently under control, switching from anICSs device with a low pulmonary deposition to onewith a high pulmonary deposition may proveadvantageous. Conversely, for patients whose dis-ease is well managed and who are using an ICSsdevice with a high pulmonary deposition, everyeffort should be made to reduce the dose to avoidunnecessary systemic side effects. The relationshipbetween the site of drug deposition in the lung andtherapeutic effect is, however, less well under-stood.8

Consistency of lung depositionDose reproducibility is an important considerationfor ICSs therapy. In vitro assessments of deviceconsistency appear to be poor predictors of lung-deposition consistency in vivo. For example, thefluticasone Diskuss inhaler has shown less varia-bility in distribution of aerosol particle sizes thanbudesonide TurbuhalerTM in in vitro simulationsand, based on this, it has been argued that greaterconsistency in lung deposition could be expectedwith the Diskuss device.35,36 However, this has notbeen borne out in vivo; conversely, TurbuhalerTM

has shown less variability in lung deposition thanthe Diskuss inhaler in children and adults.18,37

TurbuhalerTM was also found to provide greaterconsistency in terms of budesonide lung-depositionin vivo when compared with a pMDI, in spite of thefact that in vitro the variability in drug delivery wasmarkedly less for the pMDI.14 This discrepancy

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Inhaled corticosteroids in the asthma and COPD 843

between in vitro and in vivo consistency may bedue, in part, to a difference in aerosol particle sizedistributions between inhalers. Compared with theDiskuss inhaler, TurbuhalerTM delivers 3–4 times asmany fine particles, which may deposit moreconsistently and/or more peripherally in theintrapulmonary airways than larger particles. Thedifference between in vitro and in vivo resultsmay, however, simply reflect the fact that therelatively small variability seen under standardizedin vitro conditions becomes insignificant whenbiological and clinical factors (e.g. inhalationtechnique, airway geometry, and flow) are alsoconsidered.18,31

Lung deposition: misconceptions abouteffectiveness of devicesDose delivery from DPIs such as TurbuhalerTM isreliant upon patients being able to generate anadequate peak inspiratory flow to disaggregate thedrug into particles small enough to reach the lungs.For such devices, patients with large lung volumesgenerating high inspiratory flows are likely to attainhigh levels of drug deposition in the lungs. Somepatients groups—notably asthmatic children andpatients with advanced COPD—are often perceivedas being unable to generate a sufficient inspiratoryflow to achieve adequate clinical benefit frominhalation of medication via a DPI. However, arecent review of the literature7 has shown this tobe a misconception.

Contrary to popular belief, patients with acuteasthma are able to generate a high inspiratory flowthrough a DPI. The duration of the inspiratory flow,however, is shorter in this scenario due to a lowerinspiratory volume. In this situation, a DPI isactually likely to perform better than a pMDI,particularly given the problems of coordinatingactuation and inhalation during an acute asthmaexacerbation.7 In one study of 99 adults presentingto hospital with acute exacerbations of asthma,98% generated an inspiratory flow through Turbu-halerTM greater than 30 l/min, which is ideal forachieving an optimal clinical effect (only twopatients recorded 26 l/min), the mean peak in-spiratory flow being 60 l/min.38 Comparable find-ings have also been reported in studies in childrenwith asthma39 and in patients with COPD.40 Indeed,in a study of 82 children with mild–moderateasthma, all children were capable of inhalingthrough a TurbuhalerTM at a flow rate 440 l/min(mean values of 59 and 70 l/min for children aged3–6 and 7–10 years, respectively).39 In children,there appears to be significant correlation betweenlung deposition of budesonide (delivered via Tur-buhalerTM, NebuChambers or nebulizer) and the

size (diameter) of the mouth and oropharynx,41–43

while systemic exposure to the drug (i.e. lungdeposition) was similar in small children andadults.42 This implies that from a safety perspec-tive, the same doses can be used in children andadults without increasing the risk of systemicexposure. Importantly, the lower absolute lungdeposition in children is offset by a higher orallydeposited fraction, which does not contributesignificantly to the total systemic load.

Clinical efficacy and safety ofbudesonide: influence of device

Clinical efficacy

Given the differences in inhalation characteristicsand pulmonary deposition, it is not surprising thatthe various corticosteroid delivery systems alsoappear to have very different efficacy and safetyprofiles when administered to patients with asthmaor COPD. The extensive clinical trial programme forbudesonide has included all three major devicetypes, and has demonstrated good efficacy forbudesonide in the management of persistentasthma (irrespective of disease severity) in patientsof all ages, as well as in the acute asthma settingand in patients with COPD.5

pMDIs are the most established means for ICSsdelivery and have therefore been the benchmarkagainst which new corticosteroid inhalation deviceshave been judged and against which dose selectionsfor the new systems have been made. In the case ofbudesonide, results from early clinical studiescomparing the efficacy of the same nominal doseof budesonide given via pMDI or via the Turbuha-lerTM DPI showed a clear improvement in peakexpiratory flow with the TurbuhalerTM comparedwith a pMDI.44–46 Subsequent randomized trialshave calculated the difference in the dose:potencyratio of clinical efficacy between the two modes ofadministration to be approximately 2:1, indicatingthat when using TurbuhalerTM only half the nominaldose of budesonide needs to be given to achievethe same clinical efficacy as the full dose given viapMDI.21,47–49 For example, Agertoft and Pedersen21

compared the efficacy and safety of a pMDI andspacer device (Nebuhalers) with TurbuhalerTM forthe delivery of budesonide to children with chronicperennial asthma who were previously treated withbudesonide via pMDI. Initially, 241 children withasthma had their dose of budesonide optimizedduring a run-in period. Once their asthma hadstabilized, these children were then randomized to

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L. Thorsson, D. Geller844

receive budesonide at either the original dose viapMDI plus spacer or half the original dose deliveredvia TurbuhalerTM. Compared with the pMDI plusspacer, TurbuhalerTM was found to be at least aseffective in terms of peak expiratory flow measure-ments and was also associated with a reduction inb2-agonist use.

Agertoft and Pedersen33 also compared theefficacy of budesonide TurbuhalerTM and pMDI plusNebuhalers in 216 children aged 6–14 years withchronic asthma who had received budesonide for3–6 years. In this study, the budesonide dose wastitrated down until optimal asthma control wasreached. Although the mean dose of budesonideover the study period was significantly lower withTurbuhalerTM than with pMDI plus Nebuhalers

(447 mg vs. 612 mg), children treated with Turbuha-lerTM experienced significantly greater improve-ments in pulmonary function compared with thoseusing the pMDI plus spacer (Fig. 4).

A 2:1 clinical potency ratio has also beendemonstrated for budesonide via TurbuhalerTM

relative to budesonide via pMDI without spacer inadults with asthma.47 In a general practice, studyof 631 adults whose asthma was adequatelycontrolled with inhaled budesonide or beclometha-sone (200 or 400–500 mg twice daily, respectively)administered via pMDI, switching to half the dailydose of budesonide via TurbuhalerTM either oncedaily or in two divided doses was not associatedwith any loss in asthma control. Importantly, nosignificant differences were noted in peak expira-tory flow, asthma symptom scores, bronchodilatoruse, or quality of life measures between thoseremaining on their usual treatment via pMDI

0

100

200

300

400

500

600

Turbuhaler Nebuhaler Turbuhaler Nebuhaler

60

80

60

90

100

***p < 0.001***

***

Mea

n da

ily P

ulm

icor

t dos

e (µ

g)

FE

V,(

% P

redi

cted

)

Figure 4 Mean daily dose of budesonide required foroptimal asthma control and pulmonary function inchildren with asthma receiving budesonide via Turbuha-lerTM or via a pMDI plus Nebuhalers for 3–6 years.23

and those switching to half-dose budesonidevia TurbuhalerTM. Based on these findings,attempts should be made to reduce the dose ofbudesonide when patients are switched frombudesonide pMDIs to TurbuhalerTM treatment. The2:1 clinical potency ratio for TurbuhalerTM relativeto pMDI is consistent with the finding that budeso-nide lung deposition achieved with TurbuhalerTM isapproximately twice that achieved with pMDI.14

Increased adherence and ease of use for Turbuha-lerTM relative to pMDI might also contribute tothese findings.50

Nebulization provides a useful alternative modeof delivery of corticosteroids that are available as anebulizing suspension (beclomethasone and bude-sonide) in situations where a DPI or pMDI may notbe suitable. Situations where budesonide inhalationsuspension (Pulmicort Respuless) would proveuseful include:

�

Children up to 5 years of age (approved up to 8years of age in the US).

�

Patients 45 years of age who experiencedifficulty using pMDIs or DPIs.

�

Patients of any age who cannot coordinate oractivate a pMDI or DPI because of dyspnoea.

In the case of budesonide, the clinical trialprogramme of the inhalation suspension hasincluded infants and children up to 8 years ofage with asthma severity ranging from mild tomoderate. In this population, nebulized budesonideproved effective at daily doses of between 0.25and 1mg (administered as a single daily dose orin two divided doses) (Fig. 5)51,52 and hasbeen found to be equally effective both in childreno4 and X4 years of age.53 Shapiro et al.54 studiedchildren ages 4–8 years with more severe asthma,who were already receiving ICSs at baseline.Doses up to 1mg twice daily were effectiveat improving morning peak flow and reducingsymptoms and need for rescue medication.54

Budesonide delivered via nebulization has beenshown to be significantly more effectivethan placebo and sodium cromoglycate at improv-ing symptoms and reducing asthma exacerbationsin children with persistent asthma.55 In adults,high-dose budesonide (within the recommendeddose range) via nebulization (synchronized withinhalation to minimize loss of drug) is moreeffective than budesonide delivered via pMDIplus spacer in managing severe persistent asthma,thus reducing the requirement for oral steroidsand improving asthma symptoms and lung function(Fig. 6).35

ARTICLE IN PRESS

Time (weeks)

Chan

ge in a

sth

ma s

ym

pto

m s

core

fro

m b

aselin

eDaytime Night-time0

-0.1

-0.2

-0.3

-0.4

-0.5

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0

-0.1

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-0.5

-0.6

0-22-4

4-86-8

8-1010-12

0-22-4

4-86-8

8-1010-12

Place bo (n-92)Pulmicort Respules 0.25 mg once daily (n-92)Pulmicort Respules 0.25 mg twice daily (n-97)Pulmicort Respules 0.5 mg twice daily (n-98)Pulmicort Respules 1 mg otwice daily (n-93)

*p <0.05**p <0.01

***p <0.001VS placebo

***

***

**

*****

Figure 5 Mean improvement in nighttime and daytime asthma symptom scores in infants and young children treatedwith nebulized budesonide (Pulmicort Respuless) 0.25, 0.5, or 1mg once daily, or placebo for 12 weeks.52

440

420

400

320

340

360

380

PE

F

Morning Evening

**

**

**

**

p < 0.01

Pulmicort 800 µg twice dally via pMDI + Nebuhaler

Pulmicort Respules 4 mg twice dally

Pulmicort Respules 1 mg twice dally

Figure 6 Morning and evening peak expiratory flowduring twice-daily treatment with budesonide nebulizingsolution (Pulmicort Respuless) 1 or 4mg, or budesonide800 mg via pMDI with Nebuhalers, in patients withmoderate or severe unstable asthma.35

Inhaled corticosteroids in the asthma and COPD 845

Local side effects

Choice of inhalation device also has a significantimpact on the nature and extent of side effects

experienced with ICSs. Although systemic toxicitiescan occur at high doses of ICSs, in routine clinicalpractice it is the local side effects of thesedrugs—particularly hoarseness and oral candidia-sis—that are the most frequent. Local side effectscan be reduced by mouth rinsing after inhalation.Also, use of a valved holding chamber in conjunctionwith a pMDI reduces oropharyngeal deposition fromapproximately 80% of the metered dose to 10–15%.56

Since DPIs are used without spacers, there have beenconcerns that use of these devices may lead toincreased local side effects. However, data fromclinical studies with budesonide suggest the oppositeto be the case. Selroos et al.49 monitored theincidence of local adverse events in 154 patientstreated with budesonide or beclomethasone via apMDI plus large-volume spacer (Nebuhalers orVolumatics, respectively) for 2 years, after whichthey were switched to budesonide TurbuhalerTM andfollowed for a further 2 years. The incidence of localadverse events (candidiasis, hoarseness, or sorethroat or gums) in patients receiving budesonide orbeclomethasone via pMDI plus spacer was 17% and23%, respectively, decreasing to 6% (Po0:001 vs.pMDI) when the patients were switched to budeso-nide TurbuhalerTM. This large decrease was duemainly to a reduction in the incidence of hoarseness,which may be related to irritating additives andpropellants used in the pMDI.

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L. Thorsson, D. Geller846

Systemic side effects

The systemic safety profile is an important con-sideration of any treatment used long term in thecontrol of a chronic disease. If administered at highenough doses, all ICSs will produce clinicallysignificant systemic activity. The systemic sideeffects of the available ICSs when used within therecommended dose ranges have been comparedpreviously.57–60 Budesonide is the most thoroughlyinvestigated ICSs in terms of long-term tolerabil-ity.3,61–65 Specifically, long-term use of budesonideis reported to have no adverse effect on final adultheight of paediatric patients, bone mineral density,or ocular changes,3,62–65 and is the only ICSsassigned a Pregnancy Category B rating by the USFood and Drug Administration; all other ICSs remainat a Pregnancy Category C rating.

Competence, adherence, and continuity

The therapeutic effectiveness of any ICSs deliverydevice ultimately rests with the patient or care-giver, and in their ability to use the device correctly(competence) and as instructed by their physician(adherence). Indeed, it has been suggested thatadherence is the major factor determining asthmacontrol during long-term treatment.66

Poor inhaler technique is a major problem forICSs therapy, particularly for pMDIs that requirecoordination between actuation and inhalation.The cold Freons effect may also interrupt inhala-tion. Indeed, it has been estimated that as many astwo-thirds of pMDI users and healthcare profes-sionals teaching pMDI use do not perform thetechnique correctly.67,68 While poor techniqueresults in inadequate doses of medication beingadministered, this can be substantially improved bygood patient education. However, even followingproper instruction, patients of all ages may beunable to use pMDIs efficiently.69,70 Use of a spaceror a valved holding chamber in conjunction with apMDI can help coordinate actuation with inhalationand substantially reduce oropharyngeal depositionand the cold Freons effect.

For patients experiencing problems using a pMDI,a DPI such as TurbuhalerTM might be a practicalalternative. The generation of the aerosol fromTurbuhaler is breath-initiated (eliminating theproblem of coordinating inspiration with actua-tion), and the particle speed is equal to the velocityof the inspired air. This functional difference mayexplain why lung deposition is less variable whenthe drug is delivered via TurbuhalerTM comparedwith delivery via a pMDI.71

There are special considerations for optimizingaerosol delivery for infants and toddlers. Manyyoung children fuss or cry when a mask from anebulizer or holding chamber is applied to the face.However, crying significantly reduces the amount ofaerosolized drug that reaches the lungs72–74 andincreases dose-to-dose variability.75 To avoid cry-ing, some caregivers will move the mask away fromthe face and give

’’

blow-by’’ treatments. However,a poor face mask seal will result in 40–85% declinesin inhaled dose with both MDI/spacer devices 76,77

and nebulizers.78,79 Techniques that may overcomethese problems include administering the aerosolduring sleep,80 using an aerosol hood,81 or usingblow-by with a tube or mouthpiece (rather than amask) held within 4 cm of the child’s nose.82

Though no significant ocular problems have beenreported in children taking usual doses of ICSs, careshould be given to avoid direct drug exposure to theeyes of the child. New face masks are beingdesigned to reduce eye exposure.83

When selecting the optimal device for delivery ofICSs to an individual, patient preference should bea key consideration since it is one of the determi-nants of patient adherence to medication. Manycauses of non-adherence with inhaled medicationhave been identified. Those relating to the deviceitself include low portability, impracticality, anddifficulties in use. Also, reimbursement issues fordurable medical equipment (spacers, nebulizers,and compressors) may play a significant role in thechoice for many patients.

Budesonide is currently the only ICSs availablefor delivery via all three major types of devicesfor which in vivo lung deposition, pharmacokineticsand clinical efficacy have been investigated.This range of inhalation systems allows budeso-nide to be delivered effectively to patients ofall ages and asthma severities. It allows theclinician and the patient to decide as a teamwhich delivery system is best for them. Indeed,children with asthma may continue with thesame drug as they mature; e.g. infants can betreated with Pulmicort Respuless and laterswitched to budesonide TurbuhalerTM at 5–6 yearsof age, if given appropriate training.62 This con-tinuity of drug therapy throughout childhood andinto adulthood helps the caregiver develop con-fidence in the drug.

Conclusions

ICSs are the cornerstone of therapy for patientswith asthma and reduce exacerbations in patients

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Inhaled corticosteroids in the asthma and COPD 847

with COPD. Numerous studies have shown that inaddition to improving lung function and asthmasymptoms, ICSs significantly reduce the incidenceof mortality and exacerbations requiring emer-gency physician visits, oral corticosteroid bursts,and hospitalizations. Indeed, ICSs therapy is nowrecommended as first-line therapy for all patientswith persistent asthma. A range of delivery deviceshave been developed to cope with the differentclinical circumstances and patient types receivingICSs treatment. The clinical benefit of such therapyis determined by a complex interplay between thenature and extent of disease, the drug and itsformulation, the characteristics of the device, andthe patient’s ability to use the device correctly.An understanding of these factors is necessarywhen considering the most appropriate treatmentoption.

The corticosteroid, budesonide, is available fordelivery via each of the three major types ofinhalation devices, allowing physicians to select theoptimal device for a particular patient, in additionto offering continuity in drug therapy as the childgrows. When delivered by any of these devices,budesonide has been found to be effective in thetreatment of persistent asthma irrespective ofseverity and age. Efficacy has also been demon-strated in patients with acute asthma and thosewith COPD. The ability to choose the appropriateaerosol delivery system for budesonide thatmatches the individual needs of the patient willhelp achieve successful treatment of obstructiveairway diseases.

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