Comparison of Inhaled Corticosteroids: What You Need to Know in Choosing a Product

Abstract

Inhaled corticosteroids (ICS) are recommended by The National Asthma Education and Prevention Program's Expert Panel Report 3 for all levels of persistent asthma in the pediatric population. The recommended ICS doses are based on assessment of severity and control of asthma. The pharmacodynamics and pharmacokinetics of the current ICSs are reviewed. While comparable efficacy can be achieved with equipotent dosing, some of the newer ICSs, fluticasone propionate, mometasone furoate, and ciclesonide, have pharmacokinetic profiles that produce less risk of systemic effects. However, at high doses systemic activity increases with all ICSs. The clinicians need to weigh the benefits and risks of these different products and dosing schemes in their patients for optimal use.

Introduction

Corticosteroids remain the cornerstone of asthma management. Regular use of inhaled corticosteroids (ICSs) improves both domains of asthma control: impairment and risk. Impairment is improved by the reduction of day and night time symptoms, reduction of bronchial hyperresponsiveness, and improvement of lung function. Risk of exacerbations requiring urgent or emergent medical care is also reduced with use of ICS.¹ Further, ICSs are the only medications for asthma that have shown to decrease risk of death from asthma.² Current expert panel guidelines recommend the regular use of ICSs for all levels of persistent asthma in pediatric and adult population. The dose ranging recommendations are based on assessment of severity and control of asthma, which is determined by assessing both impairment and risk domains as well as relative efficacy of various ICSs. Since publication of the guidelines,¹ new products have been approved for use in children and/or have been marketed, including products using hydrofluoroalkane (HFA) as a propellant for metered dose inhalers (MDIs).

Available Products

The current ICSs that are approved by U.S. Food and Drug Administration (FDA) for use in adults and children are fluticasone propionate, available as an MDI (Flovent) and dry powder inhaler (DPI; Flovent Diskus) for children 4 years and older, beclomethasone dipropionate MDI (Qvar) for children 5 years and older, mometasone furoate DPI (Asmanex Twisthaler) for 4 years and older, ciclesonide MDI (Alvesco) for 12 years and older, budesonide DPI (Pulmicort Flexhaler) for 6 years and older, and bud esonide inhalation suspension for nebulizer (Pulmicort Respules) for 12 months to 8 years. The ICSs in combination with long-acting beta agonists are fluticasone propionate and salmeterol as DPI (Advair Diskus) and MDI (Advair HFA), budesonide and formoterol fumarate dehydrate MDI (Symbicort), and mometasone furoate and formoterol fumarate MDI (Dulera). Only Advair Diskus is approved for children 4–11 years; the others are approved for 12 years and over.

Factors Affecting Dosing

When assessing clinical comparable doses of the ICSs, potency and delivery devices need to be considered.^1,3 Modifications in chemical structure of ICSs change the binding affinity to the glucocorticoid receptor that leads to a change in potency. The same efficacy can be achieved by different ICSs when equipotent doses are used. The ICSs can differ in their potency by 4- to 6-fold.^4,5 In high doses, all ICSs can produce adverse effects due to their systemic absorption.⁶ An ideal agent is the one with high topical activity in the lungs compared with a very low systemic activity: a higher therapeutic index.

Pharmacokinetics

The pharmacokinetic properties of ICSs primarily determine the therapeutic index. The topical selectivity of ICSs may be enhanced by increasing systemic clearance, decreasing gastrointestinal bioavailability, and prolonging residence time in the lungs.^4–6 On the other hand, systemic bioavailability depends on gastrointestinal bioavailability and the amount of ICS which enters the systemic circulation via lungs (Table 1). For an ICS, such as beclomethasone dipropionate, with a significant gastrointestinal absorption, use of a valved holding-chamber (VHC) with MDI decreases oral absorption by decreasing oropharyngeal deposition, hence increasing therapeutic index.^4–6 However, use of VHC with MDI with an ICS such as fluticasone propionate—with a high first pass metabolism—can increase delivery of the medication to the lung followed by increased systemic absorption, hence decreasing therapeutic index.^5,7,8

Table 1.

Comparison of Inhaled Corticosteroids

Drug	Dosages	Lung delivery ^a	Relative equivalency ^b
Fluticasone propionate	44, 110, and 220 mcg/actuation HFA MDI, 120 actuations	20%	88 mcg
	50, 100, and 250 mcg/dose DPI, Diskus, 60 doses	15%	100 mcg
Beclomethasone dipropionate	40 and 80 mcg/actuation HFA MDI, 120 actuations	55%–60%	80 mcg
Budesonide	90 and 180 mcg/dose DPI, Flexhaler, 200 doses	15%–30%	180 mcg
	250, 500 and 1000 mcg ampules, 2 mL each	5%–8%	500 mcg
Ciclesonide	80 or 160 mcg/actuation HFA MDI	50%	80 mcg
Flunisolide	80 mcg/actuation HFA MDI, 120 actuations	68%	160 mcg
Mometasone furoate	110 and 220 mcg/dose DPI, Twisthaler, 14, 30, 60, and 120 doses	11%	110 mcg

Assuming appropriate inhalation technique.

Relative potency based upon clinical efficacy not systemic activity.^1,4,5

DPI, dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered dose inhaler.

Delivery systems

The delivery of the aerosol medication into the airway maximizes therapeutic index. There are 3 available systems of aerosol delivery in the market: MDIs, DPIs, and nebulizers. The particle size generated by each system will influence drug deposition as well as the potential dose delivered to the airways. As a result, the same chemical agent may be delivered differently with different systems. There is a decrease in delivery of fluticasone propionate delivered by DPI compared with MDI that is accentuated with the addition of a VHC. The nominal dose for an MDI is the dose that leaves an actuator of the inhaler and for a DPI is the dose that is released upon actuation of the inhaler.^4,5 The nominal dose for a nebulizer is simply the milligram amount of medication placed into the nebulizer cup. Further, the aerosol delivery of the medication to the airways may range from 10% to 60% of the nominal dose.^3,4 Nebulizers also exhibit a high variability in efficiency and particle size generation.³ The only preparation for nebulization is budesonide suspension and the optimal particle size for delivery is 2–3 μm due to the large particle size of the suspension.^3,9 Although the most commercially available jet nebulizers are suitable for delivery of budesonide suspension, ultrasonic nebulizers are not suitable.

Formulation

The change in the propellant from chlorofluorocarbon (CFC) to HFA allowed some ICSs (beclomethasone dipropionate, ciclesonide, and flunisolide) to be solubilized as opposed to being dry powder micronized suspensions. This allows reduction of the particle size, resulting in significant increase in the airways delivery (up to 4- to 8-fold difference) as well as improved distribution improving small airways deposition.^9–11 Although CFC-propelled MDIs will not be manufactured as of July 2011, HFA-based MDIs can have significant variability in drug delivery depending on solubility of the chemicals in HFA. Both beclomethasone dipropionate and ciclesonide are soluble in HFA, and HFA-propelled beclomethasone can have a lung delivery in adults of 50%–60%, whereas albuterol, fluticasone propionate, and budesonide/formoterol combinations are micronized suspensions in their HFA-propelled preparations with delivery only 10%–20% of the dose to the airways.¹

Spacer devices such as VHCs are designed to be used by patients, particularly pediatric patients who cannot coordinate actuation and inhalation. Currently, the FDA has not approved use of any MDI with VHC, not because of lack of efficacy but because FDA approval was obtained based on pivotal studies without use of VHC. Although use of VHC in pediatric patients is recommended by national guidelines,¹ it is unlikely to alter the efficacy of ICS if the MDI technique is correct. Use of different VHCs with the same MDI preparation or the same VHC with different MDI preparations can result in significantly different drug delivery to airways.^1,12 In general, the small particle HFA preparations are not affected by use of a VHC.^6,12

The DPIs require a different inhalation technique that is forceful and rapid compared with MDI. The optimal delivery from DPI depends on their internal resistance, which further determines the inspiratory flow needed to deliver the respirable particles.¹² It is an advantage for a DPI when the variability of drug delivered to the airways remains minimal over a range of inspiratory flow—which depends on patient's effort and technique—especially in pediatric patients.¹³ Asmanex Twisthaler functions at a low inspiratory flow, meaning that the amount of drug delivered is constant at inspiratory flow of 30–70 L/Min.¹⁴ However, Pulmicort Flexhaler has a 50% reduction in the respirable particles when the inspiratory flow changes from 60 to 30 L/min.¹⁵

Patient-Related Factors Affecting Response

The ICS are approved by FDA to be used twice daily except mometasone that has once daily indication for maintaining asthma control.¹⁴ However, all of the ICSs have been shown to control mild asthma with once-daily dosing and all are more effective administered twice daily.⁵ Of note, ciclesonide was unable to gain approval at once-daily dosing in children due to lack of consistent efficacy although its pharmacokinetics (lung retention and half-life) are similar to mometasone.^4,5 The response to ICSs varies among patients with first symptom improvement apparent within the first 2 weeks, reaching a maximum improvement by week 8 of treatment.^9,16–21 A few phenotypic factors have been reported to determine the response to ICSs. A favorable response to ICS has been seen in patients with family history of asthma, lower forced expiratory volume in 1 second (FEV₁), bronchodilator reversibility, increased responsiveness to methacholine bronchoprovocation, higher eosinophils, higher sputum eosinophils, higher IgE, and higher FeNO.^22–24 A diminished response to ICS has been reported with current or past smoking, smoking exposure in utero, vitamin D deficiency, and obesity.^25–34 Nonetheless, ICSs still remain the most effective treatment despite their diminished effect in reported phenotypes. Recently, certain genotypes have been associated with response to corticosteroids in some but not all studies.^35,36 Replication studies in diverse patient populations confirming these findings are needed before these data can be used in a clinical setting. It is also very important to assure adherence to ICSs when assessing response to ICS as over 80% of the patients with “difficult to treat asthma” have poor adherence.³⁷ Pharmacy refill records can be accessed to confirm adherence issues and are preferred to patient report, which tends to overestimate adherence.³⁸ Needless to say that filling a prescription does not necessarily equate to taking the medication. Hence, even pharmacy refill records are not completely foolproof.

Dose–Response Relation of ICSs

The ICSs seem to have a relatively flat dose–response curve. In adult studies, quadrupling doses of ICSs in patients with moderate to severe asthma have shown a decrease in asthma exacerbation where doubling the dose did not change the outcome.^17,39,40 In children, budesonide inhalation suspension did not consistently demonstrate more efficacy compared with placebo when the dose was doubled or quadrupled from 250 mcg twice daily.⁴¹ Similarly, in children 4–14 years old, the lung function response to fluticasone propionate and budesonide seems to plateau between 100–200 and 200–800 mcg daily, respectively.^42,43 In a recent meta-analysis of 14 clinical trials in children with mild to moderate persistent asthma, the moderate doses (300–400 mcg/day beclomethasone dipropionate equivalent) of ICSs did not provide any clinical advantage compared with low doses (100–200 mcg/day).⁴³ Generallyit takes about 4-fold difference in a dose (or potency if changing ICSs) to detect a significant change in efficacy,^{4,5,10,17,18,39,40,42–47} although some patients (∼15%–20%) will respond to doubling of the dose. Also, patients with more severe disease may require and respond better to higher starting doses.⁴⁷ This is consistent with the current EPR-3 guideline recommendations of starting the dose of ICSs by level of asthma severity followed by monitoring the response and titrating the dose up or down to achieve control with minimum required dose of ICSs.¹ The choice of ICSs is usually determined by the age of the patients, route of administration, and third-party coverage of medication. As discussed before, although different ICSs have different potencies, response to lower potency ICS can be overcome by giving equipotent doses of ICSs.

Lung Delivery and Particle Size

Recently, it has been suggested that the newer small particle ICS MDIs improve asthma control more and may be more effective in infants and young children due to enhanced delivery to the small airways.^48,49 The speculation is based on the following reports and observations: inflammation of small airways is associated with severe asthma phenotype and nocturnal asthma; small particle ICSs have improved airway delivery in infants and young children; studies with HFA beclomethasone dipropionate have shown to increase peripheral airway delivery compared with CFC preparation of beclomethasone dipropionate.^48,49 However, it is still unknown if targeting small airways with small particle ICSs will change the outcome compared with standard ICSs delivered via a nebulizer, MDI, or DPI.^48,50,51 It is also very important to consider the therapeutic index of small particle ICSs in consideration, as systemic absorption of ICSs via lungs can be increased when delivery to the lungs are increased. In 2 studies in prepubertal children, beclomethasone dipropionate HFA produced significant growth suppression compared with placebo and compared with twice of the dose of CFC beclomethasone dipropionate.^19,52 This would be expected from the increase in systemic bioavailability of HFA beclomethasone dipropionate.⁶

Once-Daily Use of ICSs

As patient's adherence to daily ICSs remains a barrier to achieve control in some patients, once-daily administration of ICSs, although not proven, has been advocated as a way to improve adherence. Currently, mometasone and budesonide have FDA approval to be used once daily. However, all other ICS may also be used once daily for the patients with mild persistent asthma on low to medium doses of ICSs. Ciclesonide is the newest ICSs and although it has been approved in Europe to be used once daily for pediatric and adult patients with asthma, it only has approval in United States to be used twice daily for patients 12 years and older. Two pivotal trials using ciclesonide once daily in children 4–11 years old with moderate to severe asthma have demonstrated inconsistent efficacy. When the results of these 2 trials were combined, a statistically significant change in FEV₁ of 2.9% for 80 mcg/day and 3.5% for 160 mcg/day of ciclesonide once daily compared with placebo was reported; however, the clinical significance of this improvement remains questionable.⁵³ Ciclesonide has demonstrated similar efficacy to low dose fluticasone propionate in children 4–11 years of age when both were administered twice daily in equipotent doses.^5,54

Effects of Long-Term Use

As important as ICSs are for the management of signs and symptoms of asthma; they have failed to demonstrate a disease-modifying role as they do not prevent the development of asthma in high-risk infants nor prevent loss of lung function or enhance the lung growth in children.^28,31,55 On the other hand, ICSs control symptoms and prevent exacerbations, whereas patients are using them but they do not seem to change the natural history of asthma. One of the most concerning safety issues with use of ICSs is the effect on growth in children and this topic has been reviewed extensively.^56,57 Although a decrease in growth velocity has been reported consistently in the first year, the effect is dependent on dose, formulation, and device, and it does not seem to be cumulative. Long-term follow-up trials of 100 mcg/day fluticasone DPI and mometasone DPI in prepubertal children did not show any significant reduction in growth compared with placebo.^6,14,58 Although trials of 40 and 160 mcg/day of ciclesonide have shown no effect on growth, further investigation is necessary since these reported doses have not consistently shown efficacy in children.⁵⁹

In conclusion, the ICSs are the most effective therapy for persistent asthma in children although they do not alter the natural history of the disease. If administered in equipotent dosages, they will all produce similar efficacy. Currently, there does not appear to be any advantage of any of the ICSs in terms of once-daily dosing or small particle generating MDIs over other MDIs or DPIs. Mometasone furoate, fluticasone propionate, and ciclesonide have pharmacokinetic properties that favor less systemic activity and clinical trials of mometasone furoate DPI and fluticasone propionate DPI but not MDI have show minimal effects on growth at doses of 100–200 mcg/day. Although ciclesonide has pharmacokinetics that can potentially improve the therapeutic index, its effect on growth has not been adequately studied. ICSs by MDI plus VHC in infants is effective, but 200 mcg/day fluticasone propionate with Aerochamber produces a reduction in growth.⁵⁵ Nebulized doses of budesonide at 500 mcg/day are free of growth reduction in infants.⁴¹ More research is needed in infants and toddlers to determine appropriate dosing of the ICSs

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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