Targeting Drugs to the Airways by Different Inhalation Devices

Targeting Drugs to the Airways byDifferent Inhalation DevicesRole of Deposition Characteristics

Jan Lötvall1 and Paul O’Byrne2

1 Department of Respiratory Medicine and Allergology, Göteborg University, Göteborg, Sweden2 Division of Respirology, Department of Medicine, McMaster University, Hamilton,

Ontario, Canada

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2791. Factors Determining Airway Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2802. Comparing Inhalation Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2813. Rotahaler vs Pressured Metered-Dose Inhaler (pMDI) . . . . . . . . . . . . . . . . . . . . . . . . . . 2824. Diskhaler vs pMDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

4.1 Salbutamol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2824.2 Salmeterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

5. Diskus (Accuhaler®) vs pMDI or Diskhaler® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2836. Turbuhaler® vs pMDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

6.1 Terbutaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2836.2 Salbutamol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2846.3 Budesonide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

7. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2868. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

Abstract Inhalation therapy has greatly improved the treatment of asthma over the lastdecades. In recent years, inhalation technology has further optimised the localdeposition of inhaled antiasthma drugs. Some studies have suggested improvedclinical efficacy, and possibly tolerability, of drugs givenwithmodern dry powderinhalers. In particular, the inhalers Turbuhaler® and Diskus® are now commonlyused to treat asthma.This review critically evaluates studies comparing the clinical efficacy of anti-

asthma drugs delivered by available powder inhalers or by pressurised metered-dose inhalers (pMDI), focusing on comparisons of the same drug given bydifferent inhalers. Results differ among studies, in part because of the inclusionof different patient groups (ideally the patients should have reversible airwaysobstruction) and use of unequal doses or artificial inhalation patterns that maynot be optimal for one of the devices. Furthermore, the use of plastic spacers withpMDIs may affect drug delivery.

REVIEW ARTICLE BioDrugs 1999 Oct; 12 (4): 279-2891173-8804/99/0010-0279/$05.50/0

© Adis International Limited. All rights reserved.

During the last 4 decades, inhalation therapy hasled to considerable improvements in the treatmentof asthma. Inhalation of antiasthma drugs was pri-marily developed to reduce the pronounced sys-temic adverse effects seen with oral therapy. Forexample, when a β-agonist given by inhalation wascompared to the drug given systemically, unwantedadverse events such as tachycardia or tremor wereshown to be greatly reduced, while both routes pro-vided a similar level of bronchodilation.[1]Even more importantly, the long term use of in-

haled instead of oral corticosteroids has been shownto greatly reduce the severe systemic adverse ef-fects seen with these drugs, including adrenal sup-pression, osteoporosis and growth retardation inchildren.[2-4] Subsequently, inhaled corticosteroidshave come to be used in the early treatment of rel-atively mild asthma. The generally increased useof inhaled therapy has stimulated efforts to developnovel devices for the administration of drug aero-sols to the airways.Pressurised metered-dose inhalers (pMDI) have

been available for many years for the administra-tion of antiasthma drugs, and most patients arecomfortable with these devices. However, coordi-nation of inhalation with activation of the pMDI iscrucial for airway deposition and concomitant air-way effects,[6-8] and this may prove to be difficultespecially in young children and the elderly. Thisproblem can, to some degree, be overcome by theuse of spacer devices, or pMDIs that are activatedby the inhalation.[9] However, the potential for en-vironmental damage by chlorofluorocarbons inconventional pMDIs has reduced their use in manycountries, and will lead to their total removal frommost markets in the near future. Recently, a numberof different easy-to-use, breath-actuated powderinhalers have been developed, which in some in-stances may deliver more drug to the airways thanthe older devices.Examples of commonly used powder inhalers

include the Turbuhaler®, the Diskhaler®, and theDiskus®/Accuhaler®, all of which are more or lessdependent on the patient achieving enough inspi-ratory effort and thus airflow to aerosolise the pow-

der.[10,11] In studies of drug delivery, aerosol profileand deposition, these dry powder inhalers have dif-ferent characteristics compared to pMDIs. For ex-ample, it has been suggested that the Turbuhaler®delivers more metered drug to the lung compart-ment than a pMDI.[12]It has been proposed that the efficacy of a spe-

cific inhaled antiasthma drug could be different ifgiven by different inhaler devices, and many com-parisons have been performed to prove or disprovesuch a hypothesis. These studies include long termcomparisons in clinical settings[13-16] as well as ex-perimental comparisons in clinical laboratories,using either β2-agonists or corticosteroids.[16-19]This review summarises the factors that deter-

mine the efficacy of inhaled antiasthma drugs de-livered from different devices. Furthermore, someproblems associated with such experimental com-parisons of devices will be highlighted, to try toexplain some of the apparent discrepancies in theresults of the studies. Only studies comparing theeffect of the same drug from different devices arediscussed, to focus on the role of the device.

1. Factors Determining Airway Drug Delivery

For any drug given by inhalation, the perfor-mance of the inhaler device is important for drugdelivery, deposition and subsequent clinical ef-fects. Optimally, the inhaled aerosols should be de-signed to deposit drug in intrapulmonary airways,not the oropharynx. However, most devices usedtoday deposit approximately 70 to 80% of the aer-osolised drug in the mouth and oropharynx and, toa variable degree, in central and peripheral in-trathoracic airways. Most inhalation devices de-liver only a fraction of the nominal dose to the lungs(7 to 30% of drug in different studies).[7,8,12,20,21] Ithas been suggested that the Turbuhaler® device de-livers approximately 20 to 30% of drug to the lung,and pMDI and Diskhaler® approximately 7 to15%.[12,20,21]However, total lung deposition is not the only

determinant of clinical efficacy. The exact site ofdeposition could also be important for efficacy, and

280 Lötvall & O’Byrne

© Adis International Limited. All rights reserved. BioDrugs 1999 Oct; 12 (4)

it is possible that this site should be different forvarious drugs with disparate effects. Delivering aninhaled drug to a precise airway site could thustheoretically improve its therapeutic ratio. It couldbe hypothesised that inflammation in the periph-eral airways should be treated with a fine particleaerosol.[22] In contrast, bronchodilators may bebetter delivered to larger airways, because this isthe primary site of airflow obstruction.It may be possible to deliver drugs more pre-

cisely by using aerosols with an exact particle size(monodispersed aerosol). As an example, it hasbeen shown that a low dose of a monodispersed drypowder aerosol of ipratropium bromide or sal-butamol, with a particle size of exactly 2.8μm(without distribution), results in more substantialbronchodilation than a standard dose from a pMDI(polydispersed aerosol).[23]Flow rates when inhaling a drug from a device

may also affect deposition and clinical efficacy.Thus, it has been suggested that pMDI aerosolsshould be inhaled slowly, whereas aerosol from drypowder devices should be inhaled with high in-spired flows.[8,11] The high inspired flows are re-quired from dry powder inhalers partly to aerosol-ise the stored powder during the exit through thedevice. However, in the normal use of these de-vices, it may be very difficult to predict exactlywhich flow the patient will use in the clinical situ-ation. For example, Borgström et al.[24] reportedthat patients using pMDIs normally inhale fromtheir device at a flow of approximately 200L/min,[24] despite the optimal flow being suggestedto be approximately 40 L/min.[8]

2. Comparing Inhalation Devices

Comparing the effect of a drug delivered by 2different inhalation devices is not an easy task, inview of the many variables that may influence theresults. Clinical experimental studies in the labo-ratory setting are aimed at optimising the inhala-tion technique for each device. However, this maycreate an artificial situation for the patient, such asthe patient trying to control their inhalation flowaccording to an on-line inhalation flow display.

The inhalation manoeuvre should therefore ideallybe comfortable for the patient and similar to thetechnique used in normal daily life.One factor of fundamental importance when

comparing the clinical performance of different in-halation devices to deliver bronchodilators is thatthe patients included in the comparison shouldhave reversible airway obstruction, and that the re-versibility is dose-dependent within the dose rangeof the drug studied. This means that it is importantto include patients who require higher doses of abronchodilator to achieve full reversibility. This iscritical because most patients with asthma respondwith full bronchodilation at very low doses of abronchodilator, so that comparing a low and a highdose that both cause full bronchodilation is quiteuseless. However, using a step-wise reversibilityas an inclusion criterion increases the likelihood ofresponses on the slope of the dose-response curve,and the different treatments will be easier to com-pare.[25] For meaningful interpretation of the data,it is thus crucial to avoid flat dose-response curves,i.e. those showing near-complete reversibility atthe lowest dose studied.[26]A comparison of 2 devices should ideally in-

clude at least 3 doses from one of the devices, and2 or 3 doses from the other device. Furthermore,the doses being compared should preferably be thesame, on amicrogram tomicrogram basis. Asmen-tioned, it is important that a dose-response isshown, and ideally that the effect of the secondtreatment is intermediate. Such dose-response re-lationships may be easier to find using bronchodi-lators, but most studies comparing different dosesof inhaled glucocorticoids often fail to show sig-nificant dose-dependent effects.[27-32]Lastly, to prove differences in device perfor-

mance in asthma, it would be important to confirmfindings in any experimental clinical study, by us-ing larger multicentre study designs. However, insuch studies, it is still important to include onlypatients with dose-related responses to the drugstudied.

Targeting Drugs to the Airways 281


3. Rotahaler® vs PressurisedMetered-Dose Inhaler (pMDI)

In the first generation of dry powder inhalers,capsules of active drug had to be placed within thedevice by hand and broken so that the drug couldbe inhaled. The efficacy of salbutamol given by onesuch device, the Rotahaler®, has been comparedwith pMDI in 2 studies.[33,34]The first study compared the effect of 4 doses

of salbutamol dry powder (50 to 400μg), with onedose of salbutamol pMDI (200μg). The effect of200μg salbutamol Rotahaler® was found to be verysimilar to 200μg of drug given by pMDI. However,in the more recent study by Zainudin and col-leagues,[34] the bronchodilatory effect of sal-butamol pMDI was found to be better than with theRotahaler®. Furthermore, this study reports highertotal lung deposition, and higher relative peripherallung deposition, of technetium-labelled Teflonparticles inhaled via the pMDI.This study is one of few comparing deposition

and effect of inhaled aerosols. These results indi-cate that the more pronounced bronchodilationwith salbutamol pMDI was achieved with thehigher deposition, arguing that the total amount ofdelivered drug to the lungs is important for effi-cacy.

4. Diskhaler® vs pMDI

TheDiskhaler® device is produced in 2 differentversions, a larger one for salbutamol and beclometh-asone dipropionate, and a smaller one for sal-meterol and fluticasone. The smaller Diskhalers®have a slightly higher inspiratory resistance,[11]which theoretically could influence the productionof the aerosol and subsequently the deposition andclinical effect.

4.1 Salbutamol

It was initially suggested that salbutamol shouldbe given at twice the dose using the larger Dis-khaler® to achieve the same effect as with a dosegiven by pMDI. However, the published experi-mental support for this supposition is weak. In fact,

there are no published studies directly comparingthe same nominal doses of salbutamol from thesedevices.In one study, the effects of 1 dose of salbutamol

from each device were compared. The doses cho-sen were 400μg for the Diskhaler® and 200μg forthe pMDI.[35] A very similar maximal bronchodi-lator effect was observed, with no difference in on-set of action or duration of effect. However, it is notknown where the doses lay on the dose-responsecurve for these specific patients, and it is impossi-ble to compare potency relationships when onlyone dose of either treatment has been utilised.Another study evaluated the speed of revers-

ibility of methacholine-induced bronchocon-striction by salbutamol given by pMDI or Dis-khaler®. In this study, the same mean onset ofaction was found for each treatment (3.8min forsalbutamol given via either device[36]). Again, 2different single doses of salbutamol were com-pared (200μg pMDI vs 400μg Diskhaler®).

4.2 Salmeterol

Three studies have compared the salmeterolDiskhaler® with pMDI.[37-39] Salmeterol is moredifficult to use for dose-response comparisons thansalbutamol, because of its slower onset of actionand longer duration of effect.[40-42] One of thesestudies suggested a dose-response relationship forthe bronchodilating effect of salmeterol,[37] in thatbronchodilation was slightly, but not significantly,better with salmeterol 12.5μg pMDI, comparedwith the same dose given by Diskhaler® [improve-ment 74 and 56L in peak expiratory flow rate(PEFR), respectively). At higher doses (87.5μg cu-mulative dose), bronchodilation was more similarwith the 2 devices. In this study, only 8 patientswere evaluated, which may have been too few tostatistically detect any significant differences be-tween the devices, at least at the higher doses.A larger study was subsequently performed in

36 patients, comparing the bronchodilating effectof 50μg salmeterol given as a single dose via the 2devices.[38] The mean maximal improvements inFEV1 were the same for the 2 devices, confirming



the similar clinical performance of salmeterol Dis-khaler® and pMDI at this comparatively highdose.[37] From a device-comparison point of view,it would have been better to compare lower dosesof salmeterol.In a larger multicentre study, the effects of

salmeterol 50μg twice daily given either as pMDIor Diskhaler® were evaluated in 162 childrenrandomised in a parallel group study.[39] Improve-ments in morning PEFR were fairly modest butagain were similar in pMDI and Diskhaler®groups.Together, these 3 studies argue that there is not

much difference in the efficacy of salmeterolpMDI and Diskhaler®, either in an experimental ora clinical setting. It is important to remember thatthese findings cannot be extrapolated to the effi-cacy of the salbutamol or beclomethasone diprop-ionate Diskhaler®, because the resistance differs inthe large and small Diskhaler® devices.[43]

5. Diskus (Accuhaler®) vs pMDI orDiskhaler®

There are, as yet, no data published as full pa-pers comparing the bronchodilator capacity ofsalbutamol Diskus® with pMDI. The developmentof the Diskus® is based on comparisons with theDiskhaler®. In one study, the speed of reversibilityof methacholine-induced bronchoconstriction wasfound to be very similar with salbutamol pMDI andDiskus®.[43] More studies are required to comparethe relative clinical performance of bronchodilat-ors given via the Diskus® compared with thepMDI.

6. Turbuhaler® vs pMDI

Two β-agonists (terbutaline and salbutamol)and a corticosteroid (budesonide) have been com-pared using the Turbuhaler® versus the pMDI.When evaluating these data, it is important to re-member that the pMDI used in the comparisons isthe one clinically available for each drug, and thesedifferent pMDIs may perform differently. Thus,terbutaline and budesonide Turbuhalers® are com-pared with the respective pMDIs (Bricanyl® and

Pulmicort®), and the salbutamol Turbuhaler® iscompared with the pMDI Ventolin®.

6.1 Terbutaline

Several comparative studies have evaluated ter-butaline in pMDI and Turbuhaler® early in the de-velopment of this dry powder device. Four studiespublished approximately 10 years ago suggest thatterbutaline Turbuhaler® and terbutaline pMDI areequivalent in a laboratory setting, both in childrenand in adults. For example, a cumulative dose-response comparison showed very similar bron-chodilating effects, microgram for microgram, ofterbutaline pMDI and Turbuhaler® in adults (fig.1).[17] This cumulative dose-response comparisonshowed greater improvement in lung function atthe higher doses compared to the lowest doses.In a second study in adults, the dose response

was not as impressive, but very similar effects ofterbutaline pMDI and Turbuhaler® were still ob-served.[16] A study in children, also using cumula-tive doses of terbutaline pMDI or Turbuhaler®,confirmed the equivalence of these devices in thispatient group.[18]In acute asthma, terbutaline Turbuhaler® seems

to be superior to terbutaline pMDI plus a plasticspacer device.[44] Briefly, in a parallel group studyin patients with acute asthma attending the emer-gency room, the effects of terbutaline Turbuhaler®and pMDI were evaluated and the inhalation flowwas monitored. Terbutaline Turbuhaler® improvedFEV1 more than terbutaline pMDI with a plasticspacer. The mean inhalation flows were reported tobe 100L through the Turbuhaler® and 111L throughthe pMDI/spacer. The lower efficacy of terbutalinepMDI/spacer versus Turbuhaler® in this study hasbeen confirmed in another study.[45]These results are not easy to explain, in view of

the 3 previous studies suggesting equivalence ofterbutaline Turbuhaler® and pMDI. However, ithas been suggested that aerosol drugs may stick tothe wall of plastic spacer devices,[46] which mayexplain the lower efficacy of the terbutaline pMDIwith a plastic spacer versus the terbutaline Turbu-haler®.



Another explanation comes from a study com-paring the lung deposition of inhaled terbutalinefrom pMDI or Turbuhaler® to the bronchodilatingeffect.[24] This was an experimental study, using thecharcoal block method to evaluate the amount ofterbutaline taken up into the systemic circulation.Inhalation flow was not only monitored but the pa-tients were also regulating their inhalation flowfrom each device. The inhalation flows chosen foreach device were 60 L/min from the Turbuhaler®and 90 L/min from the pMDI. The inhalation flowfrom the pMDI was chosen to be between the flowsuggested to be optimal for peripheral aerosol de-position[5-8] and the flow reported to be the mostcommon in a larger group of asthmatic patients.[24]Thus, it is likely that the inhalation flow from theTurbuhaler® was optimal, whereas this may not betrue for the pMDI.The bronchodilating effect of 2 doses of ter-

butaline Turbuhaler® was found to be superior tothat of the same doses of terbutaline pMDI (fig. 2).

Approximately 9% total lung deposition was seenwith both doses of terbutaline pMDI, whereas ap-proximately 18 to 21% was seen with the Turbu-haler®. Thus, in this experimental setting, the ter-butaline Turbuhaler® was found to be superior tothe terbutaline pMDI, likely due to increase in lungdeposition.[24]

6.2 Salbutamol

Several clinical experimental studies have com-pared the potency of salbutamol given either bypMDI or Turbuhaler®. In two of these studies, 50to 200μg salbutamol given by Turbuhaler® wascompared with 100 to 400μg salbutamol given bypMDI.[19,25] Both studies were very similar in de-sign but evaluated 13 and 50 patients, respectively.Approximately equal bronchodilation was seen

with half the dose of salbutamol given by Turbu-haler® compared with pMDI. The potency ratio ofsalbutamol given by the different inhalers was cal-culated to be 2 : 1, suggesting that the Turbuhaler®is a better device for delivering salbutamol to theairways (fig.3). However, one very important fac-tor may have influenced these results. Typically,inhalation flow was low from the pMDI (30 L/min)but higher from the Turbuhaler® (60 L/min). Thelow inhalation flow is considered to be optimal forthe pMDI,[8] but it has been reported that the pa-tients often use inhalation flows of up to 200 L/min

0

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ositi

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)

Fig. 2. Lung deposition of terbutaline and improvement in lungfunction in patients with reversible airflow obstruction given ter-butaline via pressurised metered dose inhaler (pMDI) orTurbuhaler® (TH) [reproduced from Borgstrom et al.,[24] with per-mission]. FEV1 = forced expiratory volume in 1 second.

00 0.25 0.5 1 2 4

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Fig. 1. Improvement in forced expiratory volume in 1 second(FEV1) in patients with reversible airflow obstruction, in an earlystudy comparing inhalation of terbutaline from pressurised me-tered dose inhaler (pMDI) and Turbuhaler® (TH) [reproducedfrom Johnsen & Rung Weeke,[17] with permission].



from the pMDI.[24] Therefore, it seems possiblethat higher inhalation flows may have better re-flected the clinical reality.An additional study has evaluated the effect of

increasing actuations of salbutamol Turbuhaler®100μg with pMDI 200μg in acute asthma, in a totalof 86 patients using a parallel group design.[47] To-tal doses were 2000μg via Turbuhaler® and4000μg via pMDI. Mean peak inhalation flow wasmeasured and found to be equally low in both pa-tient groups (47 to 49 L/min). In this clinical set-ting, the unequal doses of salbutamol were foundto be equieffective in improving lung function, in-dicating that salbutamol is better delivered fromthe Turbuhaler®.The higher efficacy of salbutamol given via the

Turbuhaler® has, however, been questioned re-cently.[25] Briefly, patients with dose-related FEV1reversibility were included in a crossover studycomparing equal, but cumulative, doses of sal-butamol given via Turbuhaler® or pMDI (200 to3200μg). Both treatments produced highly signif-icant bronchodilation versus placebo, but there

was no tendency for a difference between the 2devices (fig. 4). Furthermore, safety parameterssuch as serum potassium and heart rate were mon-itored, and found not to differ between devices,again suggesting that the 2 devices are equivalent.Another recent study has compared the protec-

tive effect of salbutamol Turbuhaler® and pMDI onmethacholine airway responsiveness.[48] Bothtreatments showed that salbutamol given by eitherdevice protected against methacholine-inducedbronchoconstriction, with no significant differencebetween the 2 devices (fig. 5).These 2 latter studies are in contrast to the pre-

vious studies comparing unequal doses of sal-butamol Turbuhaler® and pMDI, and their resultsargue that delivering salbutamol via the Turbu-haler® is as effective as delivering the drug bypMDI. Regarding systemic adverse effects, thereseems to be no advantage or disadvantage to givingsalbutamol by the Turbuhaler®.[25]

6.3 Budesonide

A number of studies have also compared theeffects of budesonide given by Turbuhaler® and

0.8250 100 200 400

0.83

0.84

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0.88

0.89

InE

vAv

FE

V1

TH50

TH2 � 100

pMDI100

pMDI2 � 200

Salbutamol dose (μg)

Fig. 3. Increase in average forced expiratory volume in 1 second( FEV1) [natural logarithm] after administration of salbutamolgiven by Turbuhaler® or pressured metered-dose inhaler(pMDI), in a crossover, double-blind study by Löfdahl et al.[19]

(reproduced with permission). The data suggest higher potencyfor salbutalmol when given by Turbuhaler® than when given bypMDI. Importantly, the inhalation procedure was >50 L/secthrough the Turbuhaler®and approximately 30 L/sec through thepMDI (see text for discussion of methodology).

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Baseline 200 400 800 1600 3200


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Fig. 4. Mean improvement in forced expiratory volume in 1 sec-ond (FEV1) after increasing doses of salbutamol given by pre-ssurised metered-dose inhaler (pMDI) or Turbuhaler® (TH). Nodifference in bronchodilating effect was observed withsalbutamol given by the 2 devices (reproduced from Mellén etal.,[25] with permission).



pMDI. Again, it should be emphasised that con-ducting potency comparisons with inhaled cortico-steroids in asthma is very difficult because of theflat dose-response curve in asthmatic patients.[27-32] Therefore, using an inhaled corticosteroid forcomparison of clinical efficacy of a drug given bydifferent inhaler devices is difficult, but has beenattempted.One study, in approximately 250 children,[13]

demonstrated that the budesonide dose required foroptimal asthma control from the Turbuhaler® wasapproximately half that required from the pMDI.Once again, budesonide from the pMDI was deliv-ered through a plastic spacer device which to somedegree may have decreased total drug delivery tothe airways. As shown in figure 6,[47] the deliveryof budesonide differs when given by standard orantistatic spacers because of the electrostaticcharge in standard spacers. Despite this problem,the study shows that, in this patient group, the drypowder inhaler is better than the alternative, whichin children is the pMDI with a plastic spacer de-vice.A second study, performed in adult patients,[14]

evaluated the efficacy of budesonide or terbutalinegiven via the Turbuhaler® or pMDI. Overall,asthma-related events occurred sooner in thepMDI-treated group than in the Turbuhaler®-treated group. For the pMDI, the PEFR dropped atleast once under 90% in 40% of patients after ap-proximately 110 days of treatment, whereas thesame change did not occur until approximately 240days in the Turbuhaler® group. Close to 90% of thepatients were treated with budesonide, and differ-ences in efficacy between the 2 devices is mostlikely due to differences in anti-inflammatory ef-fects of inhaled budesonide delivered by the 2 de-vices.

7. Discussion

Studies comparing the efficacy of bronchodilat-ors given via pMDIs or dry powder inhalers showdisparate results, depending on at least 3 differentparameters.

Firstly, it is crucial that the patients have revers-ible airflow obstruction. The reversibility must beless with a lower dose of bronchodilator andgreater with a higher dose, resulting in dose-relatedimprovements in lung function after inhalation ofdrug.Secondly, equal doses of drug from each device

should be compared, avoiding bias for any treat-ment. This is important because the slope of thedose-response curve for a β2-agonist may be differ-ent at the low versus the high range of doses. Thus,it is possible that a much lower dose of β2-agonistis required for an initial mild bronchodilation, per-haps reaching 50% of maximal improvement ofFEV1, than doses required for maximal improve-ment in FEV1.

1

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atio


Fig. 5. Mean methacholine concentration causing a 20% fall inforced expiratory volume in 1 second (PC20) in relation to pla-cebo, after treatment with salbutamol via Turbuhaler® (triangle)or pressurised metered-dose inhaler (square). The slope of thedose-response curves for each device seems to overlap (repro-duced from Wong et al.,[48] with permission).



Thirdly, the inhalation flow may influence thepattern of deposition of inhaled anti-asthma drugsfrom any device. However, monitoring and influ-encing the inhalation flow in bronchodilator stud-ies are 2 interventions that may affect the patientin an artificial way, rather than represent the clini-cal situation.Studies using bronchodilators may show differ-

ences in efficacy and potency of different inhala-tion devices because of unequal dosing or artificialinhalation patterns that are not optimal for one ofthe devices. Furthermore, the use of plastic spacersmay have influenced the results, since the deliveryof drug may be decreased by drug sticking to theinner spacer wall.[46]The goal of developing novel inhalation devices

must be primarily to improve the therapeutic ratioof the delivered drug, to deliver as much as possi-ble to the diseased airways and as little as possibleto the systemic circulation. However, most sys-temic adverse effects of inhaled drugs may origi-nate from the inhaled portion of the drug. There-

fore, improved distribution of drug throughout theairway tree may lead to better efficacy and possiblyallow reduced total dosages, which in turn may de-crease adverse effects. Testing whether a deviceprovides such benefits is, however, a complex taskrequiring several types of experimental clinicalstudies.When comparing inhalation devices, it is im-

portant to initially perform clinical experimentalstudies in a clinical laboratory setting, to establishthe efficacy of drug delivered from the devices inan ideal situation. However, such studies do notfirmly establish efficacy differences between de-vices, and larger subsequent multicentre studiesmust also be performed. Thus, the optimal compar-ison of bronchodilators delivered from different in-halation devices should be performed in a substan-tial number of patients with highly reversibleairflow obstruction, using several equal doses ofdrug from each device, in a clinical setting, andpreferably in a crossover design. Furthermore, ad-verse effects of the delivered drug should be eval-uated in parallel with the beneficial efficacy pa-rameters, for evaluation of therapeutic ratio.However, the ideal comparison of a dry powderdevice with pMDI remains to be performed for anyanti-asthma drug.

8. Conclusion

Overall, it has been difficult to demonstrate dif-ferences of major clinical importance in efficacyand safety between presently available inhalationdevices, using the currently available informationand study designs. For this reason, issues such asease of use, individual preference and convenienceare important in deciding which inhalation deviceto use in the everyday treatment of asthma. Thegreatest improvement in inhalation therapy proba-bly lies ahead, with future innovative devices de-livering small monodispersed aerosols targeted tospecific airway levels.

Acknowledgements

Dr Jan Lötvall was financed by grants from King OscarII Foundation, and by Herman Krefting’s Foundation.

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Fig. 6. Delivery of budesonide via a nonprimed and primed plas-tic spacer, showing that such devices can affect the delivery ofaerosal and, thus drug (reproduced from Barry and O’Calla-ghan,[47] with permission).



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Correspondence and reprints: Dr Jan Lötvall, The LungPharmacology Group, Guldhedsgatan 10A, S-413 46Gothenburg, Sweden.E-mail: [email protected]



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