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

REVIEW ARTICLE

© 2007 Adis Data Information BV. All rights reserved.

Inhaled Corticosteroids in Children with Asthma Pharmacologic Determinants of Safety and Efficacy and Other Clinical Considerations Tanya Gulliver,1 Ronald Morton2 and Nemr Eid2 1 2

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

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 1. Pharmacology of Different Inhaled Corticosteroids (ICS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 1.1.1 Lung Deposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 1.1.2 Pulmonary Residency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 1.1.3 Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 1.1.4 Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 1.1.5 Plasma Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 1.1.6 Volume of Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 1.2 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 1.2.1 Receptor Affinity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 1.2.2 Prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 1.2.3 Dose Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 2. Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3. Efficacy of Different ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3.1 Compared with Nonsteroidal Asthma Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3.2 Compared with Other ICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3.3 Disease-Modifying Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 4. Potential Adverse Effects of Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 4.1 Adrenal Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 4.2 Growth Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

Abstract

The role of inhaled corticosteroids (ICS) in the treatment of childhood asthma has been well established. An ideal corticosteroid should demonstrate high pulmonary deposition and residency time, in addition to a low systemic bioavailability and rapid systemic clearance. The lung depositions of the ICS have been compared, with beclomethasone (beclometasone)-hydrofluoroalkane (HFA) and ciclesonide showing the highest lung deposition. Lung deposition is influenced by not only the inhalation device and type of propellant (HFA or chlorofluorocarbon), but also by whether the aerosol is a solution or suspension, and the particle size of the respirable fraction. Pulmonary residency time increases when budesonide and des-ciclesonide undergo reversible fatty acid esterification. The bioavailability of the drug depends on the oral bioavailable fraction and the amount 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 and mometasone have a high protein binding fraction (98–99%). The volume of distribution (Vd) is proportional to the 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

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both the receptor binding affinity and the dose-response curve. Among the ICS, fluticasone and mometasone have the highest receptor binding affinity (1800 and 2200, respectively), followed by budesonide at 935 (relative to 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. One study suggests that early intervention with ICS reduces the loss in lung function (forced expiratory volume in 1 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 doses ICS have shown little suppression of the adrenal pituitary axis, in high doses the potential for significant adrenal suppression and adrenal crisis exists. Several longitudinal studies evaluating the effect of ICS on growth have shown a small decrement in growth velocity (≈1–2cm) during the first year of treatment. However, when investigators followed children treated with budesonide for up to 10 years, no change in target adult height was noted. In conclusion, the development of optimal delivery devices for young children, as well as optimizing favorable pharmacokinetic properties of ICS should be priorities for future childhood asthma management.

Asthma is becoming a global problem. It is estimated that around 300 million people in the world currently have asthma and that this figure will increase to 400 million by 2025.[1] In the US, approximately 12% of children currently have asthma.[2] Asthma is characterized by extensive airway inflammation causing lumen narrowing and obstruction to airflow. These pathologic changes result in the characteristic symptoms of wheezing, dyspnea, chest tightness, and cough. Inhaled corticosteroids (ICS) are established first-line preventive agents for children with persistent asthma.[3] Compared with oral corticosteroids, ICS are effective and safe therapeutic agents that act by exerting a local anti-inflammatory effect at the site of pathology. Airway inflammation is thus effectively treated with a reduced risk of adverse drug reactions. Seven different ICS are currently available on the market for clinical use: triamcinolone, budesonide, flunisolide, beclomethasone (beclometasone), fluticasone propionate, mometasone, and ciclesonide. Mometasone and ciclesonide are relatively recent drugs approved for clinical use. Optimizing delivery of medication to the lungs is an ongoing challenge affecting the efficacy and safety of each of the above drugs. Changes to propellants have recently evolved because of concerns regarding their effect on the environment. The newer hydrofluoroalkane (HFA)-based formulations have shown some advantages compared with the older chlorofluorocarbon (CFC) propellants.[4,5] Major determinants of efficacy relate to the dissolution of drug into a solution rather than solid particles suspended in a liquid (suspension). Dry powder inhalers (DPIs) do not use a propellant. The force generated by a patient’s inhalation technique delivers the drug to the lungs. © 2007 Adis Data Information BV. All rights reserved.

This review outlines the important pharmacokinetic and pharmacodynamic issues that determine drug performance when assessing the safety and efficacy of ICS in children. It also raises important clinical considerations faced by researchers and clinicians. It is not intended as a guide for selection of a particular drug for treatment. 1. Pharmacology of Different Inhaled Corticosteroids (ICS) Assessment of the efficacy and safety of a drug requires some knowledge of its pharmacokinetic and pharmacodynamic properties; evaluating these features among drugs of the same class also assists in interpreting clinical comparisons. To understand a particular ICS, the clinician needs to be familiar with multiple pharmacologic parameters. These include deposition with the specific chosen device in the specific targeted age group, the relative potency of the compound, the ability of the compound to be retained in lung tissue, and the effect this has on dosage administration frequency. The clinician also needs to be familiar with the total systemic bioavailability, clearance rate or elimination halflife when delivered via a specific device (not just oral availability), and finally, the extent of distribution in peripheral tissue as well as the presence or absence of active metabolites. An ideal ICS will have maximal efficacy reflecting high lung deposition and long pulmonary residency times. This should be coupled with an excellent safety profile achieved through a low total systemic bioavailability and rapid systemic clearance (table I). Pediatr Drugs 2007; 9 (3)

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1.1 Pharmacokinetics

1.1.1 Lung Deposition

For ICS to exert their optimal anti-inflammatory effects, it is thought that high total lung deposition and deposition in the small airways is desirable. Evidence suggests that the small airways play a major role in the pathophysiology of asthma. Treatment of inflammation throughout the bronchial tree may improve asthma control and small airway patency.[33-37] It has also been suggested that effective treatment of childhood asthma may prevent progressive functional changes that continue into adulthood.[38-41] Several factors influence lung deposition. These include: (i) the physical properties of the ICS; (ii) delivery device; (iii) particle size; and (iv) a patient’s characteristics such as age, asthma severity, and cognitive or developmental status. Figure 1 illustrates differences in overall lung deposition among the various ICS. When delivered by a metered-dose inhaler (MDI) with an HFA propellant, the much higher percentage lung deposition with inhaled beclomethasone and ciclesonide compared with fluticasone propionate is attributable to the physical properties of fluticasone propionate (i.e. it is a suspension rather than a solu-

tion). HFA suspensions and their CFC counterparts retain the same particle size, deposition, and efficacy profiles when emitted. However, HFA solutions are emitted as extra-fine aerosols. Fine particles have been shown to penetrate more effectively into the peripheral regions of the lung. Radiolabeled deposition studies by Leach et al.[6] revealed a diffuse pattern of deposition within the lung with HFA-beclomethasone whereas CFC-beclomethasone was confined to the central airways. Comparisons of HFA solutions with their CFC counterparts have demonstrated equivalent control of moderately severe asthma at approximately half the daily dose. The HFA solution also demonstrated a good safety profile. These data imply an improved therapeutic ratio for these newer preparations.[4] For drugs with low lung deposition such as CFC-beclomethasone, significantly more drug is deposited in the oropharynx; in this instance, the degree of oral bioavailability influences safety. For drugs such as fluticasone propionate that have high first-pass metabolism,[7] extensive absorption from the lung can result in elevated systemic activity. Several different inhalers are used to deliver ICS in pediatric asthma. However, it is the particle size generated by the device 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 (active metabolite)

Formulation

Solution (HFA) Suspension (CFC)

Suspension

Suspension (HFA)

Solution

Suspension

Solution

Inhaled form

Inactive parent compound

Active compound

Active compound

Active compound

Active compound

Inactive parent compound

Active: BMP Particle size (MMAD) of respirable fraction (μm)

1.1 (HFA) 3.5–4 (CFC)

2.4–4

No data

1.2 (HFA) 3.8 (CFC)

2.8–2.6 (HFA) 2.8–3.2 (CFC)

1.1–2.1

Pulmonary deposition (%)

60 (HFA) 4–7 (CFC)

28 (HFA)

13.9 (HFA)

39 (HFA)

16 (HFA) 12–13 (CFC) 10 (DPI)

52 (HFA)

Receptor-binding affinity[22,30-32] 53 (BDP) (relative to dexamethasone) 1345 (BMP) [RRA = 100]

935

2200

180

1800

12/1200 (inactive/ active metabolites)

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

Oral bioavailability (%)

26

11–14

<1

7

2.7 (BMP) a

14 (INH) <1

<1

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. © 2007 Adis Data Information BV. All rights reserved.

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MDI-CFC MDI-HFA DPI

Overall lung deposition (%)

60 50 40 30 20 10 0 BDP

FLU

FP

BUD

TA

CIC

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

size distribution (or mass median aerodynamic diameter) for lung deposition ranges from 1μm to 5μm.[46] Smaller particles (<1μm) are engulfed by the alveolar macrophages, while larger particles (>5μm) are swept out of the airways by the mucociliary apparatus. HFA propellants coupled with solubilized drugs in MDIs produce the greatest proportion of small particles in aerosols.[47] This allows deep penetration of the drug into the small airways and potentially more effective treatment. Leach et al.[8] reported that 50–60% of beclomethasone solution was delivered to the lungs using a HFA propellant, signifying better overall lung deposition compared with CFC-fluticasone propionate (12–13%) and CFCbeclomethasone (4%). Even patients with poor inhaler technique were able to obtain at least 37% lung deposition. In contrast, 90–94% of CFC-beclomethasone suspension is deposited in the oropharynx.[6] In addition to greater treatment effects, improved lung delivery of ICS may lead to clinically important, systemic adverse effects if a nominal 1 : 1 dose switch is made between CFC and HFA formulations.[48] Therefore, only half the CFCequivalent dose is recommended for HFA preparations. DPIs produce larger particles compared with MDIs. The fine particle fraction (particle size <4.7μm) of fluticasone propionate delivered by a MDI and spacer has been calculated at 85.2% of the emitted dose, whereas the fine particle fraction was 10.9% from a DPI. Consequently, pulmonary delivery of medications via a MDI and spacer is 4.3-fold that of a DPI.[49] Studies also demonstrate significantly greater plasma concentrations of fluticasone propionate and cortisol suppression with MDI administration compared with DPI delivery.[9] Pulmonary delivery of nebulized budesonide to young children and infants depends on the nebulizer type and patients factors such as small tidal volume, small airways, rapid respiration, inability to hold breath with inhaled medication, nose © 2007 Adis Data Information BV. All rights reserved.

breathing, aversion to external devices such as masks, spacers, and nebulizers and, finally, cognitive ability. Deposition is extremely variable and vastly different to that of drug delivery by handheld devices. Healthy volunteers inhale almost twice as much fluticasone propionate from an aerosol than patients with moderately severe asthma.[50] This suggests that the disease process itself can affect the efficacy and safety profile of some treatments. It may also account for some of the variability of efficacy seen between patients. The potential risk for adverse effects from the same dose of a particular ICS may therefore vary between individuals. However, no differences in plasma levels have been observed in healthy or asthmatic individuals with the more water-soluble budesonide.[51] In children, confounding issues exist in the assessment of efficacy and safety of ICS. These issues mostly relate to variations in drug delivery. Consistency of drug delivery is frequently difficult to achieve in large-scale studies. Use of various inhalation devices depend on the developmental age of the child. For example, younger children require a mask with a spacer or nebulizer while older children learn to use a mouthpiece for more efficient drug delivery. In addition, important physiologic factors determining bronchial deposition in small children are breathing frequency, tidal volume, and the degree of bronchial and nasal obstruction, since inhalation is primarily via the nose.[52] 1.1.2 Pulmonary Residency

An ICS with a prolonged pulmonary residency time is advantageous for efficacy and safety reasons: the time for the drug to exert an anti-inflammatory effect is extended in the lungs and absorption into the systemic circulation is delayed. A primary defense mechanism of the lung, the mucociliary escalator, will remove deposited particles from the lung by the upward beating of cilia. Molecules with a larger particle size will be removed by mucociliary clearance when deposited in the larger segmental bronchi and will, therefore, have a shorter pulmonary residency time. The dissolution rate of particles is also an important factor influencing the length of time an inhaled drug remains in the lung.[53] In general, drugs dissolved in solution are absorbed quickly into the systemic circulation.[54] Another important factor to consider when discussing pulmonary residency is lipophilicity. Lipophilic drugs pass easily across the cellular membranes of phospholipids to the interior of the cells, where the glucocorticoid receptors are located. This allows greater pulmonary retention and longer duration of action.[47] However, lipophilicity may negatively affect safety, as highly lipophilic molecules may accumulate in other body tissues, resulting in unwanted systemic side effects. The lipophilicity of selected ICS Pediatr Drugs 2007; 9 (3)

Safety and Efficacy of Inhaled Corticosteroids in Children

listed in descending ranking order is: ciclesonide, fluticasone propionate, beclomethasone, budesonide, and triamcinolone.[47,55] Intracellular fatty acid conjugation traps a drug in the lung. Such a reaction is thought to provide a slow-release reservoir of drug in lung tissue and to improve topical efficacy. Budesonide and the active metabolite of ciclesonide, des-ciclesonide, undergo this reversible reaction.[56,57] 1.1.3 Bioavailability

The bioavailability of ICS impacts considerably on safety. High pulmonary deposition and low oral bioavailability are desirable features. The amount of drug deposited in the mouth and swallowed depends on the delivery device used. This fraction of drug plus the degree of first-pass metabolism in the liver and gastrointestinal tract lining determines oral bioavailability.[58] Oral bioavailabilities of various ICS are presented in table I. The total systemic bioavailability of an inhaled drug is the sum of the oral bioavailable fraction and the amount absorbed directly from the pulmonary vasculature without undergoing metabolism or inactivation. The risk of systemic adverse effects, therefore, will not be eliminated by the use of the newer ICS that have minimal oral bioavailability. For example, fluticasone propionate has minimal oral bioavailability yet has significant potential for systemic adverse effects. This is due entirely to the absorption of drug deposited in the lungs. Similarly, the use of a spacer device or small-particle aerosols will reduce oral deposition yet has the potential to increase systemic bioavailability.[59,60]

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Ciclesonide and des-ciclesonide along with mometasone have the highest protein binding (98–99%).[14,62] The protein binding of fluticasone propionate is lower at 90%.[63] Despite this difference in binding and the theoretical safety benefits of mometasone over fluticasone propionate, both drugs have similar systemic effects at microgram-equivalent doses.[64] Fardon et al.[64] showed significant suppression of overnight urinary cortisol/creatinine levels with high and medium doses of mometasone and fluticasone propionate. Protein binding reversibility is a possible explanation for these observations. Reversible binding is also consistent with other features of mometasone, including its large volume of distribution (Vd) and its rapid clearance. 1.1.6 Volume of Distribution

Vd is proportional to the lipophilicity and tissue binding of an ICS. An ICS with a large Vd will also have a prolonged elimination half-life. A large Vd and consequently high tissue binding can result in drug accumulation in tissue stores and may increase systemic activity once the drug diffuses into the circulatory system. High lipophilicity of an ICS slows diffusion from the lung into the systemic circulation, enhancing its respiratory effects relative to its systemic effects. As outlined in table I, BMP has a large Vd at 400L, which is exceeded only by the active metabolite of ciclesonide, des-ciclesonide, the Vd of which reaches almost 1200L. Budesonide and fluticasone propionate have a Vd of 183L and 318L, respectively.[12,19,50] 1.2 Pharmacodynamics

1.1.4 Clearance

The fate of an ICS once it reaches the systemic circulation is highly relevant to its efficacy-safety profile. Rapid systemic clearance minimizes systemic adverse effects and increases pulmonary targeting. Most ICS are swiftly metabolized by the liver and clearance is similar to hepatic blood flow. Clearance rates for beclomethasone-17-monopropionate (a major metabolite of beclomethasone), budesonide, and fluticasone propionate are 120 L/h,[10] 84 L/h,[11] and 69 L/h,[12] respectively. The active metabolite of ciclesonide, des-ciclesonide, has reportedly very high apparent clearance values (228 L/h).[13] This illustrates the presence of additional extra-hepatic clearance mechanisms that act to improve its safety profile.[53] 1.1.5 Plasma Protein Binding

The binding of ICS to albumin decreases the free fraction of drug in the circulation and is thought to prevent it from exerting a receptor-mediated effect outside the lung. Protein binding levels of des-ciclesonide, budesonide, and fluticasone propionate have been shown to correlate well with degrees of cortisol suppression.[61] © 2007 Adis Data Information BV. All rights reserved.

1.2.1 Receptor Affinity

Glucocorticoid receptors are present throughout the body. While corticosteroid binding with lung receptors produces a beneficial effect in asthma, serious adverse effects are produced by the same mechanism in other parts of the body. ICS with higher binding affinities, such as fluticasone propionate, induce an effect at lower concentrations.[65] This feature can be a safety concern. 1.2.2 Prodrugs

It can be assumed that an ICS activated at the site of pathology has better pulmonary targeting and minimal local adverse reactions. Two ICS metabolized to active compounds within the lung are ciclesonide and beclomethasone; the active forms are desciclesonide and beclomethasone monopropionate, respectively.[10,56] Unfortunately, there is no evidence to show that activation occurs only within the lung. It is possible that esterases outside pulmonary tissue may lead to increased systemic bioavailability of the active compound. Pediatr Drugs 2007; 9 (3)

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1.2.3 Dose Response

The dose-response relationship of inhaled fluticasone propionate is the most thoroughly examined of the ICS for both efficacy and adrenal function in children with asthma. A systematic review[66] revealed that little evidence exists for increased efficacy in children with doses >400μg. Systemic effects also increase at higher doses. In terms of efficacy, the dose-response curve plateaued between 100 and 200 μg/day with some additional benefit for children with severe asthma seen with 400 μg/day. Dosages of fluticasone propionate >400 μg/day resulted in adrenal suppression in a small but clinically significant number of children. 2. Pharmacogenetics Pharmacogenetics is the study of the role of genetic determinants in the variable, interindividual response to medications. It is estimated that genetics account for 20–95% of variability in drug disposition and effects.[67] To date, numerous examples have been reported of heritable differences in pharmacokinetics resulting in varied response to medications.[68] Unlike non-genetic factors that influence drug response, inherited determinants generally remain stable throughout an individual’s lifetime. Large interindividual variation in the treatment response to ICS is well known,[69] and it is likely that a substantial fraction of the variance has a genetic basis.[70] It follows, therefore, that the potential for adverse effects is also subject to influence from an individual’s genetic make-up. Unfortunately, to date, there are few replicable associations and the percentage of phenotypic variance explained by these associations for ICS therapy is low. However, future research is progressing to ‘individualize’ asthma therapy by tailoring treatment based on a patient’s genes for maximal benefit and minimal adverse effects.[71] 3. Efficacy of Different ICS

3.1 Compared with Nonsteroidal Asthma Medications

A range of pharmacologic therapies has been developed to prevent and control asthma symptoms and acute exacerbations, and to relieve airflow obstruction. In comparative studies, ICS have proven to be the most consistently effective anti-inflammatory agents for the long-term management of asthma. Compared with as-needed, long-acting β2-adrenoceptor agonists over a 4-month period, regular inhaled triamcinolone resulted in significantly fewer treatment failures and exacerbations as well as significant reductions in airway inflammatory markers (nitric © 2007 Adis Data Information BV. All rights reserved.

oxide and sputum eosinophils). Symptoms and quality-of-life measures were similar in both groups.[72] In children, evidence for the regular use of long-acting β2-adrenoceptor agonists is deficient. There is considerable concern regarding their use in adults in whom post-marketing studies demonstrate a 1.71 (95% CI 1.01, 2.89) total relative risk of asthma exacerbations, death, or a life-threatening event with the use of salmeterol compared with placebo.[73,74] No pediatric studies have proven that long-acting β2-adrenoceptor agonists protect against exacerbations[75] or even provide a bronchodilator effect with regular use.[76] One study has shown deterioration in forced expiratory volume in 1 second (FEV1) with salmeterol monotherapy in children.[3,77] Another study in children demonstrated lesser improvement in lung function, symptoms, and use of other asthma medication compared with ICS therapy.[78] A comparative 12-month trial of theophylline in adults and children demonstrated its inferiority to ICS in terms of symptom control, airway hyper-reactivity, and exacerbation rate. Distressing adverse events were also significantly increased with more headaches, anxiety, and gastrointestinal symptoms reported with theophylline.[79] Evidence from the CAMP (Childhood Asthma Management Program) study, a long-term, randomized, placebo-controlled trial of nedocromil (8mg twice daily) compared with budesonide (200μg twice daily) showed significantly greater improvements in asthma symptoms, frequency of exacerbations, and use of rescue medications in children aged >5 years receiving budesonide compared with placebo. Nedocromil significantly reduced urgent care visits (16 vs 22 per 100 person-years) and courses of prednisone when compared with placebo. Overall, inhaled budesonide improved airway responsiveness and provided better control of asthma than placebo or nedocromil.[40] Similarly, significantly greater symptom control, fewer exacerbations, and less use of other asthma medications was reported with nebulized budesonide compared with cromolyn sodium (sodium cromoglicate) in 335 younger children, aged 2–6 years.[80] The leukotriene receptor antagonist, montelukast, as preventative therapy in children aged 6–14 years, is associated with a modest improvement in rescue-free days. When compared with inhaled fluticasone propionate (100μg twice daily) in a 12-month, randomized, double-blind trial, fluticasone propionate was superior in most outcomes including lung function, quality of life, and βadrenoceptor agonist use.[81] 3.2 Compared with Other ICS

There is no consensus on methods for comparing the clinical efficacy of different ICS. Potency, estimates of lung and systemic Pediatr Drugs 2007; 9 (3)

Safety and Efficacy of Inhaled Corticosteroids in Children

bioavailability, as well as lung deposition are not true measures of the differences between ICS. The preponderance of evidence suggests that these agents are not equipotent on a microgram basis. The most recent Expert Panel Report Guidelines for the Diagnosis and Management of Asthma[82] state that fluticasone propionate is more potent than beclomethasone and budesonide, which in turn are more potent than triamcinolone and flunisolide. Ciclesonide has similar clinical efficacy as fluticasone propionate in a microgram-equivalent total dose given once daily.[83,84] Clinical trials are often thought to be the most useful method of comparing ICS. However, such trials are not always clinically relevant and must include patients known to be responsive to ICS. No randomized comparative clinical trials between the ICS have been performed in children. Only by demonstrating a dose response can two different formulations be compared. Cost, compliance, and patient preference are other determinants of clinical effectiveness that are rarely properly assessed in asthma clinical trials. 3.3 Disease-Modifying Effects

It is now beyond dispute that many adults who have a history of persistent childhood asthma have irreversible lung function deficits.[85] Studies suggest early intervention in childhood may improve the outlook for lung function in the long term. O’Byrne et al.[86] demonstrated once-daily treatment with low-dose budesonide improved FEV1 in patients with recent-onset, persistent asthma, and reduced the loss of lung function over 3 years. Ulrik and Backer[41] noted an association between the degree of bronchodilator reversibility in patients at enrollment and the presence of non-reversible airway obstruction at 10 years. Although data confirm early intervention and long-term ICS therapy offers significant benefit to children with asthma, the possibility that improved control of airway inflammation early in the course of the disease reduces the decline in lung function and prevents the development of irreversible obstruction has not yet been proven. The study by Guilbert et al.[87] provides contrasting evidence that treatment with ICS in early life does not alter the natural history of asthma as effects did not carry over after the drug was stopped during the third study year. It is unknown whether continuous use, as recommended, has any substantial benefit on airway remodeling. 4. Potential Adverse Effects of Glucocorticoids 4.1 Adrenal Suppression

Significant adrenal suppression with conventional ICS doses rarely appears in clinical practice. However, when ICS are used © 2007 Adis Data Information BV. All rights reserved.

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long term at high doses, the potential for adrenal suppression becomes real. Trials evaluating the effect of an ICS on the hypothalamic-pituitary adrenal (HPA) axis are influenced by several factors; it is important to consider sources of variability both within and among trials. Factors including test sensitivity, degree of airway obstruction, and delivery device, in addition to the dose and type of ICS used can potentially affect the level of adrenal suppression detected and must be taken into account when interpreting HPA-axis results in research or practice. A major limitation in the assessment of adrenal function is that, in many studies, a single measurement of morning plasma cortisol levels is made. Although this can be helpful if abnormal, it has been recognized as an insensitive and variable measure of adrenal insufficiency.[42,43] Twelve- or 24-hour urinary cortisol or poststimulation serum cortisol responses are more sensitive measures.[42,88-90] Although debated, the area under the concentrationtime curve (AUC) has been reported as the most accurate method for assessing adrenal suppression by corticosteroids. It is derived from serum cortisol concentrations plotted against time. If an ICS dosage regimen does not show any significant cortisol suppression based on 24-hour serum AUC values, it can be assumed that the treatment is safe and unlikely to present any clinically relevant safety concerns with respect to systemic corticosteroid activity.[91] Twenty-four hour urine collections, a useful non-invasive test for children, correlate well with the AUC of serum cortisol, but reproducibility of results is compromised by inadequate supervision and incomplete collections.[92] HPA-axis suppression correlates with the incidence of systemic adverse effects with high-dose ICS. Cortisol measures may therefore act as a sensitive and quantifiable surrogate marker to identify potential adverse effects of ICS therapy.[93] Complete suppression of the HPA-axis resulting in adrenal crisis is the most serious adverse effect of ICS and may result in death.[58,94] Previously thought to be a very rare occurrence, a survey of 2912 consultant pediatricians and adult endocrinologists published in 2002 in the UK reported adrenal crisis in 33 cases (28 children). These patients had received ICS at dosages of 500–2000 μg/day;[95] 94% of patients had received fluticasone propionate and 6% CFC-beclomethasone. Although differences in HPA-axis function exists among various ICS, doses of budesonide <200μg or equivalent daily are usually not associated with any significant suppression of the HPA axis in children.[40] Encouragingly, clinical studies in adults investigating the potential for adrenal suppression with the use of the newer ICS, ciclesonide, have failed to show any significant effect on serum or 24-hour urinary cortisol levels at dosages up to 640 μg/day given in the morning or evening.[96-98] Whether the potential for other Pediatr Drugs 2007; 9 (3)

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systemic effects will be unlikely, as has been suggested,[93] is yet to be determined. 4.2 Growth Effects

Growth suppression is a potential adverse effect of oral corticosteroid use in children with asthma. Glucocorticoids alter growth hormone secretion and local insulin-like growth factor-1 production leading to growth retardation.[99] At least 1 year of longitudinal growth data is necessary to accurately assess the effects of different treatments on growth velocity in children.[100] However, long-term data are absolutely needed to ascertain the full effects of ICS on growth. Several long-term longitudinal studies have documented growth velocity with the use of ICS. The CAMP study[40] followed 1041 children with mild-to-moderate asthma treated with either budesonide, nedocromil, or placebo for 4–6 years. The mean increase in height was less (1.1cm) in the budesonide group compared with the placebo group. The major effect in growth velocity occurred within the first year of treatment; no difference in growth velocity was observed in subsequent years. A long-term cohort study showed no difference in attained adult height between age- and sex-matched children with asthma who were either treated or not treated with ICS.[101] These results were confirmed by Agertoft and Pedersen[102] who followed 142 asthmatic children treated with inhaled budesonide (mean daily dose 412μg) for 3–13 years. They found that the target adult height was reached in the patients, as for the control individuals, with no ultimate effect on adult height. Most recently, Guilbert et al.[87] studied 285 children aged 2–3 years at high risk for asthma. The children were randomly assigned to receive either placebo or fluticasone propionate (88μg twice daily) for 2 years followed by 1 year without study medication. The mean increase in height was 1.1cm less at 24 months in the fluticasone propionate group but by the end of the trial, the height increase was 0.7cm less. Overall, inhaled fluticasone propionate reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively. 5. Conclusion The preponderance of evidence supports the National Asthma Education and Prevention Program pediatric asthma treatment recommendations[103] that ICS therapy in children offers the best control for persistent asthma. Unfortunately, in the community, misunderstanding of the role of asthma medications and fear of untoward adverse effects may reduce compliance to therapy, potentially resulting in poor asthma control and increased risk of severe asthma events.[104] Although high doses of ICS are asso© 2007 Adis Data Information BV. All rights reserved.

ciated with an increased risk of adverse events, monitoring of growth and adrenal function as well as gradual reduction to the lowest effective dose will limit these events. The potential of adverse effects from oral corticosteroids are undoubtedly, far greater. Currently available ICS possess an excellent efficacy and safety profile in children when used within the guidelines. These guidelines outline a stepwise approach to asthma therapy commencing with proper assessment of asthma severity, initiation of preventative therapy, and titrating ICS to the lowest possible dose, while keeping the frequency and severity of asthma symptoms at bay. Future developments aimed at optimizing drug delivery and enhancing favorable pharmacodynamic and pharmacokinetic properties of ICS will serve to further improve the therapeutic profile of these valuable asthma medications. Acknowledgments 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, Inc., AstraZeneca, Merck, Genetech, Chiron, Corus Pharma, and ScheringPlough; and R. Morton has received consultancies from AstraZeneca and MedImmune, and grants from Chiron and Corus Pharma.

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Correspondence: Prof. Nemr Eid, Department of Pediatrics, 571 South Floyd Street, Suite 414, Louisville, KY 40202, USA. E-mail: [email protected] Pediatr Drugs 2007; 9 (3)