inhaled corticosteroids in children with asthma

Pediatr Drugs 2007; 9 (3): 185-194REVIEW ARTICLE 1174-5878/07/0003-0185/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Inhaled Corticosteroids in Children with AsthmaPharmacologic Determinants of Safety and Efficacy and OtherClinical Considerations

Tanya Gulliver,1 Ronald Morton2 and Nemr Eid2

1 John Hunter Children’s Hospital, Newcastle, New South Wales, Australia2 University of Louisville School of Medicine, Louisville, Kentucky, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1851. Pharmacology of Different Inhaled Corticosteroids (ICS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871.1.1 Lung Deposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871.1.2 Pulmonary Residency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1881.1.3 Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1891.1.4 Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1891.1.5 Plasma Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1891.1.6 Volume of Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

1.2 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1891.2.1 Receptor Affinity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1891.2.2 Prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1891.2.3 Dose Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

2. Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1903. Efficacy of Different ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

3.1 Compared with Nonsteroidal Asthma Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1903.2 Compared with Other ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1903.3 Disease-Modifying Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

4. Potential Adverse Effects of Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1914.1 Adrenal Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1914.2 Growth Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

The role of inhaled corticosteroids (ICS) in the treatment of childhood asthma has been well established. AnAbstractideal corticosteroid should demonstrate high pulmonary deposition and residency time, in addition to a lowsystemic bioavailability and rapid systemic clearance. The lung depositions of the ICS have been compared, withbeclomethasone (beclometasone)-hydrofluoroalkane (HFA) and ciclesonide showing the highest lung depo-sition. Lung deposition is influenced by not only the inhalation device and type of propellant (HFA orchlorofluorocarbon), but also by whether the aerosol is a solution or suspension, and the particle size of therespirable fraction. Pulmonary residency time increases when budesonide and des-ciclesonide undergo revers-ible fatty acid esterification. The bioavailability of the drug depends on the oral bioavailable fraction and theamount absorbed directly from the pulmonary vasculature. The clearance rate of des-ciclesonide is very high(228 L/h), increasing its safety profile by utilizing extra-hepatic clearance mechanisms. Both des-ciclesonide andmometasone have a high protein binding fraction (98–99%). The volume of distribution (Vd) is proportional tothe lipophilicity of the drug, with the Vd of fluticasone being 332L compared with 183L for budesonide.Increasing the Vd will also increase the elimination half-life of a drug. The pharmacodynamics of ICS depend on

186 Gulliver et al.

both the receptor binding affinity and the dose-response curve. Among the ICS, fluticasone and mometasonehave the highest receptor binding affinity (1800 and 2200, respectively), followed by budesonide at 935 (relativeto dexamethasone = 100).

Compared with other nonsteroid asthma medications (long-acting β-agonists, theophylline, and montelukast)ICS have proven superiority in improving lung function, symptom-free days, and inflammatory markers. Onestudy suggests that early intervention with ICS reduces the loss in lung function (forced expiratory volume in1 second) over 3 years. Whether airway remodeling is reduced or prevented in the long term is unknown.Potential adverse drug effects of ICS include adrenal and growth suppression. While in low-to-medium dosesICS have shown little suppression of the adrenal pituitary axis, in high doses the potential for significant adrenalsuppression and adrenal crisis exists. Several longitudinal studies evaluating the effect of ICS on growth haveshown a small decrement in growth velocity (≈1–2cm) during the first year of treatment. However, wheninvestigators followed children treated with budesonide for up to 10 years, no change in target adult height wasnoted.

In conclusion, the development of optimal delivery devices for young children, as well as optimizingfavorable pharmacokinetic properties of ICS should be priorities for future childhood asthma management.

Asthma is becoming a global problem. It is estimated that This review outlines the important pharmacokinetic and phar-around 300 million people in the world currently have asthma and macodynamic issues that determine drug performance when as-that this figure will increase to 400 million by 2025.[1] In the US, sessing the safety and efficacy of ICS in children. It also raisesapproximately 12% of children currently have asthma.[2] important clinical considerations faced by researchers and

clinicians. It is not intended as a guide for selection of a particularAsthma is characterized by extensive airway inflammationcausing lumen narrowing and obstruction to airflow. These patho- drug for treatment.logic changes result in the characteristic symptoms of wheezing,dyspnea, chest tightness, and cough. 1. Pharmacology of Different Inhaled

Inhaled corticosteroids (ICS) are established first-line preven- Corticosteroids (ICS)tive agents for children with persistent asthma.[3] Compared withoral corticosteroids, ICS are effective and safe therapeutic agents

Assessment of the efficacy and safety of a drug requires somethat act by exerting a local anti-inflammatory effect at the site of

knowledge of its pharmacokinetic and pharmacodynamic proper-pathology. Airway inflammation is thus effectively treated with a

ties; evaluating these features among drugs of the same class alsoreduced risk of adverse drug reactions.

assists in interpreting clinical comparisons. To understand a par-Seven different ICS are currently available on the market for

ticular ICS, the clinician needs to be familiar with multiple phar-clinical use: triamcinolone, budesonide, flunisolide, beclometha-

macologic parameters. These include deposition with the specificsone (beclometasone), fluticasone propionate, mometasone, and

chosen device in the specific targeted age group, the relativeciclesonide. Mometasone and ciclesonide are relatively recent

potency of the compound, the ability of the compound to bedrugs approved for clinical use.

retained in lung tissue, and the effect this has on dosage adminis-Optimizing delivery of medication to the lungs is an ongoing

tration frequency. The clinician also needs to be familiar with thechallenge affecting the efficacy and safety of each of the above

total systemic bioavailability, clearance rate or elimination half-drugs. Changes to propellants have recently evolved because of

life when delivered via a specific device (not just oral availability),concerns regarding their effect on the environment. The newer

and finally, the extent of distribution in peripheral tissue as well ashydrofluoroalkane (HFA)-based formulations have shown some

the presence or absence of active metabolites.advantages compared with the older chlorofluorocarbon (CFC)An ideal ICS will have maximal efficacy reflecting high lungpropellants.[4,5] Major determinants of efficacy relate to the disso-

deposition and long pulmonary residency times. This should belution of drug into a solution rather than solid particles suspendedcoupled with an excellent safety profile achieved through a lowin a liquid (suspension). Dry powder inhalers (DPIs) do not use atotal systemic bioavailability and rapid systemic clearance (tablepropellant. The force generated by a patient’s inhalation techniqueI).delivers the drug to the lungs.

© 2007 Adis Data Information BV. All rights reserved. Pediatr Drugs 2007; 9 (3)

Safety and Efficacy of Inhaled Corticosteroids in Children 187

1.1 Pharmacokinetics tion). HFA suspensions and their CFC counterparts retain the sameparticle size, deposition, and efficacy profiles when emitted. How-ever, HFA solutions are emitted as extra-fine aerosols. Fine par-

1.1.1 Lung Deposition ticles have been shown to penetrate more effectively into theFor ICS to exert their optimal anti-inflammatory effects, it is peripheral regions of the lung. Radiolabeled deposition studies by

thought that high total lung deposition and deposition in the small Leach et al.[6] revealed a diffuse pattern of deposition within theairways is desirable. Evidence suggests that the small airways play lung with HFA-beclomethasone whereas CFC-beclomethasonea major role in the pathophysiology of asthma. Treatment of was confined to the central airways. Comparisons of HFA solu-inflammation throughout the bronchial tree may improve asthma tions with their CFC counterparts have demonstrated equivalentcontrol and small airway patency.[33-37] It has also been suggested

control of moderately severe asthma at approximately half thethat effective treatment of childhood asthma may prevent progres-

daily dose. The HFA solution also demonstrated a good safetysive functional changes that continue into adulthood.[38-41]

profile. These data imply an improved therapeutic ratio for theseSeveral factors influence lung deposition. These include: (i) the

newer preparations.[4] For drugs with low lung deposition such asphysical properties of the ICS; (ii) delivery device; (iii) particle

CFC-beclomethasone, significantly more drug is deposited in thesize; and (iv) a patient’s characteristics such as age, asthma

oropharynx; in this instance, the degree of oral bioavailabilityseverity, and cognitive or developmental status. Figure 1 illus-

influences safety. For drugs such as fluticasone propionate thattrates differences in overall lung deposition among the various

have high first-pass metabolism,[7] extensive absorption from theICS. When delivered by a metered-dose inhaler (MDI) with an

lung can result in elevated systemic activity.HFA propellant, the much higher percentage lung deposition with

Several different inhalers are used to deliver ICS in pediatricinhaled beclomethasone and ciclesonide compared with fluti-asthma. However, it is the particle size generated by the devicecasone propionate is attributable to the physical properties of

fluticasone propionate (i.e. it is a suspension rather than a solu- that is the most relevant to pulmonary targeting.[44,45] Ideal particle

Table I. Pharmacokinetic and pharmacodynamic properties of various inhaled corticosteroids[6-29]

Parameter BDP BUD MF FL FP CIC/des-CIC (activemetabolite)

Formulation Solution (HFA) Suspension Suspension Solution Suspension SolutionSuspension (CFC) (HFA)

Inhaled form Inactive parent Active Active Active Active Inactive parentcompound compound compound compound compound compound

Active: BMP

Particle size (MMAD) of 1.1 (HFA) 2.4–4 No data 1.2 (HFA) 2.8–2.6 (HFA) 1.1–2.1respirable fraction (μm) 3.5–4 (CFC) 3.8 (CFC) 2.8–3.2 (CFC)

Pulmonary deposition (%) 60 (HFA) 28 (HFA) 13.9 (HFA) 39 (HFA) 16 (HFA) 52 (HFA)4–7 (CFC) 12–13 (CFC)

10 (DPI)

Receptor-binding affinity[22,30-32] 53 (BDP) 935 2200 180 1800 12/1200 (inactive/(relative to dexamethasone) 1345 (BMP) active metabolites)[RRA = 100]

Protein binding (%) 87 88 98–99 80 90 99/99

Volume of distribution (L) 400 (BMP) 183 332 174 318 –/1190a

Clearance (L/h) 120 (BMP) 84 53.5 87–109 69 –/396a

Elimination half-life (h) 0.5 (BDP) 2.8 4.5 1.6 7.8 (IV) 0.7/3.5a

2.7 (BMP) 14 (INH)

Oral bioavailability (%) 26 11–14 <1 7 <1 <1

a Apparent.

BDP = beclomethasone (beclometasone); BMP = beclomethasone-17-monopropionate; BUD = budesonide; CFC = chlorofluorocarbon; CIC = ciclesonide;des-CIC = des-ciclesonide; DPI = dry powder inhaler; FL = flunisolide; FP = fluticasone propionate via CFC metered-dose inhaler; HFA =hydrofluoroalkane; INH = inhaled; IV = intravenous; MF = mometasone; MMAD = mass median aerodynamic diameter; RRA = relative receptor affinity.


188 Gulliver et al.

breathing, aversion to external devices such as masks, spacers, andnebulizers and, finally, cognitive ability. Deposition is extremelyvariable and vastly different to that of drug delivery by handhelddevices.

Healthy volunteers inhale almost twice as much fluticasonepropionate from an aerosol than patients with moderately severeasthma.[50] This suggests that the disease process itself can affectthe efficacy and safety profile of some treatments. It may alsoaccount for some of the variability of efficacy seen betweenpatients. The potential risk for adverse effects from the same doseof a particular ICS may therefore vary between individuals. How-ever, no differences in plasma levels have been observed inhealthy or asthmatic individuals with the more water-solublebudesonide.[51]

In children, confounding issues exist in the assessment ofefficacy and safety of ICS. These issues mostly relate to variations

0

10

20

30

40

50

60

BDP FLU FP BUD TA CIC

Ove

rall

lung

dep

ositi

on (

%)

MDI-CFCMDI-HFADPI

Fig. 1. Comparative overall lung deposition of inhaled corticosteroids ad-ministered by a metered-dose inhaler-chlorofluorocarbon (MDI-CFC), MDI-hydrofluoroalkane (HFA), or dry powder inhaler (DPI).[9,19,42,43] BDP = be-clomethasone (beclometasone); BUD = budesonide; CIC = ciclesonide;FLU = flunisolide; FP = fluticasone propionate; TA = triamcinolone.

in drug delivery. Consistency of drug delivery is frequently diffi-cult to achieve in large-scale studies. Use of various inhalationsize distribution (or mass median aerodynamic diameter) for lungdevices depend on the developmental age of the child. For exam-deposition ranges from 1μm to 5μm.[46] Smaller particles (<1μm)ple, younger children require a mask with a spacer or nebulizerare engulfed by the alveolar macrophages, while larger particleswhile older children learn to use a mouthpiece for more efficient(>5μm) are swept out of the airways by the mucociliary apparatus.drug delivery. In addition, important physiologic factors determin-HFA propellants coupled with solubilized drugs in MDIs pro-ing bronchial deposition in small children are breathing frequency,duce the greatest proportion of small particles in aerosols.[47] Thistidal volume, and the degree of bronchial and nasal obstruction,allows deep penetration of the drug into the small airways andsince inhalation is primarily via the nose.[52]potentially more effective treatment. Leach et al.[8] reported that

50–60% of beclomethasone solution was delivered to the lungs1.1.2 Pulmonary Residencyusing a HFA propellant, signifying better overall lung depositionAn ICS with a prolonged pulmonary residency time is advanta-compared with CFC-fluticasone propionate (12–13%) and CFC-

geous for efficacy and safety reasons: the time for the drug to exertbeclomethasone (4%). Even patients with poor inhaler techniquean anti-inflammatory effect is extended in the lungs and absorp-were able to obtain at least 37% lung deposition. In contrast,tion into the systemic circulation is delayed. A primary defense90–94% of CFC-beclomethasone suspension is deposited in themechanism of the lung, the mucociliary escalator, will removeoropharynx.[6] In addition to greater treatment effects, improveddeposited particles from the lung by the upward beating of cilia.lung delivery of ICS may lead to clinically important, systemicMolecules with a larger particle size will be removed by mucocili-adverse effects if a nominal 1 : 1 dose switch is made betweenary clearance when deposited in the larger segmental bronchi andCFC and HFA formulations.[48] Therefore, only half the CFC-will, therefore, have a shorter pulmonary residency time. Theequivalent dose is recommended for HFA preparations.dissolution rate of particles is also an important factor influencingDPIs produce larger particles compared with MDIs. The finethe length of time an inhaled drug remains in the lung.[53] Inparticle fraction (particle size <4.7μm) of fluticasone propionategeneral, drugs dissolved in solution are absorbed quickly into thedelivered by a MDI and spacer has been calculated at 85.2% of thesystemic circulation.[54]emitted dose, whereas the fine particle fraction was 10.9% from a

DPI. Consequently, pulmonary delivery of medications via a MDI Another important factor to consider when discussing pulmon-and spacer is 4.3-fold that of a DPI.[49] Studies also demonstrate ary residency is lipophilicity. Lipophilic drugs pass easily acrosssignificantly greater plasma concentrations of fluticasone propion- the cellular membranes of phospholipids to the interior of the cells,ate and cortisol suppression with MDI administration compared where the glucocorticoid receptors are located. This allows greaterwith DPI delivery.[9] Pulmonary delivery of nebulized budesonide pulmonary retention and longer duration of action.[47] However,to young children and infants depends on the nebulizer type and lipophilicity may negatively affect safety, as highly lipophilicpatients factors such as small tidal volume, small airways, rapid molecules may accumulate in other body tissues, resulting inrespiration, inability to hold breath with inhaled medication, nose unwanted systemic side effects. The lipophilicity of selected ICS



listed in descending ranking order is: ciclesonide, fluticasone Ciclesonide and des-ciclesonide along with mometasone havepropionate, beclomethasone, budesonide, and triamcinolone.[47,55] the highest protein binding (98–99%).[14,62] The protein binding of

fluticasone propionate is lower at 90%.[63] Despite this differenceIntracellular fatty acid conjugation traps a drug in the lung.in binding and the theoretical safety benefits of mometasone overSuch a reaction is thought to provide a slow-release reservoir offluticasone propionate, both drugs have similar systemic effects atdrug in lung tissue and to improve topical efficacy. Budesonidemicrogram-equivalent doses.[64] Fardon et al.[64] showed signif-and the active metabolite of ciclesonide, des-ciclesonide, undergoicant suppression of overnight urinary cortisol/creatinine levelsthis reversible reaction.[56,57]

with high and medium doses of mometasone and fluticasonepropionate. Protein binding reversibility is a possible explanation1.1.3 Bioavailabilityfor these observations. Reversible binding is also consistent withThe bioavailability of ICS impacts considerably on safety. Highother features of mometasone, including its large volume of distri-pulmonary deposition and low oral bioavailability are desirablebution (Vd) and its rapid clearance.features. The amount of drug deposited in the mouth and swal-

lowed depends on the delivery device used. This fraction of drug1.1.6 Volume of Distributionplus the degree of first-pass metabolism in the liver and gastroin-

testinal tract lining determines oral bioavailability.[58] Oral Vd is proportional to the lipophilicity and tissue binding of anbioavailabilities of various ICS are presented in table I. ICS. An ICS with a large Vd will also have a prolonged elimina-

tion half-life. A large Vd and consequently high tissue binding canThe total systemic bioavailability of an inhaled drug is the sumresult in drug accumulation in tissue stores and may increaseof the oral bioavailable fraction and the amount absorbed directlysystemic activity once the drug diffuses into the circulatory sys-from the pulmonary vasculature without undergoing metabolismtem. High lipophilicity of an ICS slows diffusion from the lungor inactivation. The risk of systemic adverse effects, therefore, willinto the systemic circulation, enhancing its respiratory effectsnot be eliminated by the use of the newer ICS that have minimalrelative to its systemic effects. As outlined in table I, BMP has aoral bioavailability. For example, fluticasone propionate has mini-large Vd at 400L, which is exceeded only by the active metabolitemal oral bioavailability yet has significant potential for systemicof ciclesonide, des-ciclesonide, the Vd of which reaches almostadverse effects. This is due entirely to the absorption of drug1200L. Budesonide and fluticasone propionate have a Vd of 183Ldeposited in the lungs. Similarly, the use of a spacer device orand 318L, respectively.[12,19,50]small-particle aerosols will reduce oral deposition yet has the

potential to increase systemic bioavailability.[59,60]

1.2 Pharmacodynamics1.1.4 Clearance

The fate of an ICS once it reaches the systemic circulation1.2.1 Receptor Affinityis highly relevant to its efficacy-safety profile. Rapid systemicGlucocorticoid receptors are present throughout the body.clearance minimizes systemic adverse effects and increases pul-

While corticosteroid binding with lung receptors produces a bene-monary targeting. Most ICS are swiftly metabolized by the liverficial effect in asthma, serious adverse effects are produced by theand clearance is similar to hepatic blood flow. Clearance ratessame mechanism in other parts of the body. ICS with higherfor beclomethasone-17-monopropionate (a major metabolite ofbinding affinities, such as fluticasone propionate, induce an effectbeclomethasone), budesonide, and fluticasone propionate areat lower concentrations.[65] This feature can be a safety concern.120 L/h,[10] 84 L/h,[11] and 69 L/h,[12] respectively.

The active metabolite of ciclesonide, des-ciclesonide, has re-portedly very high apparent clearance values (228 L/h).[13] This 1.2.2 Prodrugs

illustrates the presence of additional extra-hepatic clearance mech- It can be assumed that an ICS activated at the site of pathologyanisms that act to improve its safety profile.[53] has better pulmonary targeting and minimal local adverse reac-

tions. Two ICS metabolized to active compounds within the lung1.1.5 Plasma Protein Binding are ciclesonide and beclomethasone; the active forms are des-The binding of ICS to albumin decreases the free fraction of ciclesonide and beclomethasone monopropionate, respective-

drug in the circulation and is thought to prevent it from exerting a ly.[10,56] Unfortunately, there is no evidence to show that activationreceptor-mediated effect outside the lung. Protein binding levels of occurs only within the lung. It is possible that esterases outsidedes-ciclesonide, budesonide, and fluticasone propionate have been pulmonary tissue may lead to increased systemic bioavailability ofshown to correlate well with degrees of cortisol suppression.[61] the active compound.


190 Gulliver et al.

1.2.3 Dose Response oxide and sputum eosinophils). Symptoms and quality-of-lifeThe dose-response relationship of inhaled fluticasone propion- measures were similar in both groups.[72]

ate is the most thoroughly examined of the ICS for both efficacy In children, evidence for the regular use of long-acting β2-adre-and adrenal function in children with asthma. A systematic re- noceptor agonists is deficient. There is considerable concern re-view[66] revealed that little evidence exists for increased efficacy in garding their use in adults in whom post-marketing studies demon-children with doses >400μg. Systemic effects also increase at strate a 1.71 (95% CI 1.01, 2.89) total relative risk of asthmahigher doses. In terms of efficacy, the dose-response curve exacerbations, death, or a life-threatening event with the use ofplateaued between 100 and 200 μg/day with some additional salmeterol compared with placebo.[73,74] No pediatric studies havebenefit for children with severe asthma seen with 400 μg/day. proven that long-acting β2-adrenoceptor agonists protect againstDosages of fluticasone propionate >400 μg/day resulted in adrenal exacerbations[75] or even provide a bronchodilator effect withsuppression in a small but clinically significant number of chil- regular use.[76] One study has shown deterioration in forced expir-dren. atory volume in 1 second (FEV1) with salmeterol monotherapy in

children.[3,77] Another study in children demonstrated lesser im-2. Pharmacogenetics provement in lung function, symptoms, and use of other asthma

medication compared with ICS therapy.[78]

Pharmacogenetics is the study of the role of genetic determi- A comparative 12-month trial of theophylline in adults andnants in the variable, interindividual response to medications. It is children demonstrated its inferiority to ICS in terms of symptomestimated that genetics account for 20–95% of variability in drug control, airway hyper-reactivity, and exacerbation rate. Distres-disposition and effects.[67] To date, numerous examples have been sing adverse events were also significantly increased with morereported of heritable differences in pharmacokinetics resulting in headaches, anxiety, and gastrointestinal symptoms reported withvaried response to medications.[68] Unlike non-genetic factors that theophylline.[79]

influence drug response, inherited determinants generally remain Evidence from the CAMP (Childhood Asthma Managementstable throughout an individual’s lifetime. Program) study, a long-term, randomized, placebo-controlled trial

Large interindividual variation in the treatment response to ICS of nedocromil (8mg twice daily) compared with budesonideis well known,[69] and it is likely that a substantial fraction of the (200μg twice daily) showed significantly greater improvements invariance has a genetic basis.[70] It follows, therefore, that the asthma symptoms, frequency of exacerbations, and use of rescuepotential for adverse effects is also subject to influence from an medications in children aged >5 years receiving budesonide com-individual’s genetic make-up. pared with placebo. Nedocromil significantly reduced urgent care

Unfortunately, to date, there are few replicable associations and visits (16 vs 22 per 100 person-years) and courses of prednisonethe percentage of phenotypic variance explained by these associa- when compared with placebo. Overall, inhaled budesonide im-tions for ICS therapy is low. However, future research is progress- proved airway responsiveness and provided better control of asth-ing to ‘individualize’ asthma therapy by tailoring treatment based ma than placebo or nedocromil.[40] Similarly, significantly greateron a patient’s genes for maximal benefit and minimal adverse symptom control, fewer exacerbations, and less use of other asth-effects.[71]

ma medications was reported with nebulized budesonide com-pared with cromolyn sodium (sodium cromoglicate) in 335 young-

3. Efficacy of Different ICS er children, aged 2–6 years.[80]

The leukotriene receptor antagonist, montelukast, as prevent-ative therapy in children aged 6–14 years, is associated with a3.1 Compared with Nonsteroidal Asthma Medicationsmodest improvement in rescue-free days. When compared withinhaled fluticasone propionate (100μg twice daily) in a 12-month,A range of pharmacologic therapies has been developed torandomized, double-blind trial, fluticasone propionate was superi-prevent and control asthma symptoms and acute exacerbations,or in most outcomes including lung function, quality of life, and β-and to relieve airflow obstruction. In comparative studies, ICSadrenoceptor agonist use.[81]have proven to be the most consistently effective anti-inflamma-

tory agents for the long-term management of asthma.Compared with as-needed, long-acting β2-adrenoceptor ago- 3.2 Compared with Other ICS

nists over a 4-month period, regular inhaled triamcinolone resultedin significantly fewer treatment failures and exacerbations as well There is no consensus on methods for comparing the clinicalas significant reductions in airway inflammatory markers (nitric efficacy of different ICS. Potency, estimates of lung and systemic



bioavailability, as well as lung deposition are not true measures of long term at high doses, the potential for adrenal suppressionthe differences between ICS. The preponderance of evidence becomes real. Trials evaluating the effect of an ICS on the hypo-suggests that these agents are not equipotent on a microgram basis. thalamic-pituitary adrenal (HPA) axis are influenced by severalThe most recent Expert Panel Report Guidelines for the Diagnosis factors; it is important to consider sources of variability bothand Management of Asthma[82] state that fluticasone propionate is within and among trials. Factors including test sensitivity, degreemore potent than beclomethasone and budesonide, which in turn of airway obstruction, and delivery device, in addition to the doseare more potent than triamcinolone and flunisolide. Ciclesonide and type of ICS used can potentially affect the level of adrenalhas similar clinical efficacy as fluticasone propionate in a micro- suppression detected and must be taken into account when inter-gram-equivalent total dose given once daily.[83,84] preting HPA-axis results in research or practice.

Clinical trials are often thought to be the most useful method of A major limitation in the assessment of adrenal function is that,comparing ICS. However, such trials are not always clinically in many studies, a single measurement of morning plasma cortisolrelevant and must include patients known to be responsive to ICS. levels is made. Although this can be helpful if abnormal, it hasNo randomized comparative clinical trials between the ICS have been recognized as an insensitive and variable measure of adrenalbeen performed in children. Only by demonstrating a dose res- insufficiency.[42,43] Twelve- or 24-hour urinary cortisol or post-ponse can two different formulations be compared. Cost, com-

stimulation serum cortisol responses are more sensitive mea-pliance, and patient preference are other determinants of clinical

sures.[42,88-90] Although debated, the area under the concentration-effectiveness that are rarely properly assessed in asthma clinical

time curve (AUC) has been reported as the most accurate methodtrials.

for assessing adrenal suppression by corticosteroids. It is derivedfrom serum cortisol concentrations plotted against time. If an ICS3.3 Disease-Modifying Effectsdosage regimen does not show any significant cortisol suppression

It is now beyond dispute that many adults who have a history of based on 24-hour serum AUC values, it can be assumed that thepersistent childhood asthma have irreversible lung function defi- treatment is safe and unlikely to present any clinically relevantcits.[85] Studies suggest early intervention in childhood may im- safety concerns with respect to systemic corticosteroid activity.[91]

prove the outlook for lung function in the long term. O’Byrne Twenty-four hour urine collections, a useful non-invasive test foret al.[86] demonstrated once-daily treatment with low-dose budeso- children, correlate well with the AUC of serum cortisol, butnide improved FEV1 in patients with recent-onset, persistent asth- reproducibility of results is compromised by inadequate supervi-ma, and reduced the loss of lung function over 3 years. Ulrik and sion and incomplete collections.[92]

Backer[41] noted an association between the degree of bronchodi- HPA-axis suppression correlates with the incidence of systemiclator reversibility in patients at enrollment and the presence of

adverse effects with high-dose ICS. Cortisol measures may there-non-reversible airway obstruction at 10 years.

fore act as a sensitive and quantifiable surrogate marker to identifyAlthough data confirm early intervention and long-term ICS potential adverse effects of ICS therapy.[93] Complete suppression

therapy offers significant benefit to children with asthma, the of the HPA-axis resulting in adrenal crisis is the most seriouspossibility that improved control of airway inflammation early in adverse effect of ICS and may result in death.[58,94] Previouslythe course of the disease reduces the decline in lung function and

thought to be a very rare occurrence, a survey of 2912 consultantprevents the development of irreversible obstruction has not yet

pediatricians and adult endocrinologists published in 2002 in thebeen proven. The study by Guilbert et al.[87] provides contrasting

UK reported adrenal crisis in 33 cases (28 children). These pa-evidence that treatment with ICS in early life does not alter the

tients had received ICS at dosages of 500–2000 μg/day;[95] 94% ofnatural history of asthma as effects did not carry over after the drug

patients had received fluticasone propionate and 6% CFC-beclo-was stopped during the third study year. It is unknown whether

methasone. Although differences in HPA-axis function existscontinuous use, as recommended, has any substantial benefit on

among various ICS, doses of budesonide <200μg or equivalentairway remodeling.

daily are usually not associated with any significant suppression ofthe HPA axis in children.[40]

4. Potential Adverse Effects of GlucocorticoidsEncouragingly, clinical studies in adults investigating the po-

tential for adrenal suppression with the use of the newer ICS,4.1 Adrenal Suppression

ciclesonide, have failed to show any significant effect on serum or24-hour urinary cortisol levels at dosages up to 640 μg/day givenSignificant adrenal suppression with conventional ICS dosesin the morning or evening.[96-98] Whether the potential for otherrarely appears in clinical practice. However, when ICS are used


192 Gulliver et al.

systemic effects will be unlikely, as has been suggested,[93] is yet ciated with an increased risk of adverse events, monitoring ofto be determined. growth and adrenal function as well as gradual reduction to the

lowest effective dose will limit these events. The potential of4.2 Growth Effects adverse effects from oral corticosteroids are undoubtedly, far

greater.Growth suppression is a potential adverse effect of oral cortico-

Currently available ICS possess an excellent efficacy and safe-steroid use in children with asthma. Glucocorticoids alter growth

ty profile in children when used within the guidelines. Thesehormone secretion and local insulin-like growth factor-1 produc-

guidelines outline a stepwise approach to asthma therapy com-tion leading to growth retardation.[99] At least 1 year of longitudi-

mencing with proper assessment of asthma severity, initiation ofnal growth data is necessary to accurately assess the effects of

preventative therapy, and titrating ICS to the lowest possible dose,different treatments on growth velocity in children.[100] However,

while keeping the frequency and severity of asthma symptoms atlong-term data are absolutely needed to ascertain the full effects of

bay. Future developments aimed at optimizing drug delivery andICS on growth.

enhancing favorable pharmacodynamic and pharmacokineticSeveral long-term longitudinal studies have documented properties of ICS will serve to further improve the therapeutic

growth velocity with the use of ICS. The CAMP study[40] followed profile of these valuable asthma medications.1041 children with mild-to-moderate asthma treated with eitherbudesonide, nedocromil, or placebo for 4–6 years. The mean Acknowledgmentsincrease in height was less (1.1cm) in the budesonide groupcompared with the placebo group. The major effect in growth No sources of funding were used to assist in the preparation of this review.

N. Eid has received consultancies, honoraria, or grants from IVAX Research,velocity occurred within the first year of treatment; no differenceInc., AstraZeneca, Merck, Genetech, Chiron, Corus Pharma, and Schering-in growth velocity was observed in subsequent years. A long-termPlough; and R. Morton has received consultancies from AstraZeneca and

cohort study showed no difference in attained adult height be-MedImmune, and grants from Chiron and Corus Pharma.

tween age- and sex-matched children with asthma who were eithertreated or not treated with ICS.[101] These results were confirmed

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Asthma Education and Prevention Program: quick reference. NAEPP Expert E-mail: [email protected]


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