New asthma drugs: small molecule inhaled corticosteroids

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Small-particle inhaled corticosteroid (ICS) metered-dose inhalers were recently developed to treat asthma as part of the CFC to HFA propellant switch mandated by the Montreal Protocol. Two such ICS, beclomethasone dipropionate (BDP) and ciclesonide (CIC), are available in the United States and are formulated in HFA solutions. A major advantage of small-particle ICS is that they have improved total lung deposition and consequently, effective asthma control is achieved at lower daily doses than the large-particle ICS. Another advantage of small-particle ICS is that they are able to reach the small airways and consequently, may result in increased efficacy. Indeed, recent studies have demonstrated the effect of small-particle ICS on asthmatic inflammation in the small airways. Another advantage of small-particle ICS is that they may have an improved safety profile. Small-particle inhalers generally deposit decreased amounts of drug in the oropharynx than their CFC counterparts possibly resulting in a lower incidence of oropharyngeal candidiasis. However, growth studies and most HPA studies do not support improved safety on the basis of particle size alone and some studies suggest even higher systemic bioavailability and safety risk with smaller particles, depending on the molecule and the formulation. Further efficacy and safety studies are clearly warranted to determine any potential advantages of small-particle ICS, particularly in long-term disease modification where large-particle ICS have failed, and in infants and pre-schoolers, in whom airway delivery is problematic with current formulations.

Introduction

Small-particle inhaled corticosteroid (ICS) metered-dose inhalers were recently developed to treat asthma as part of the CFC to HFA propellant switch mandated by the Montreal Protocol (Table 1). Two such ICS, beclomethasone dipropionate (BDP) and ciclesonide (CIC), are available in the United States and are formulated in HFA solutions. The transition to HFA propellant alone is not sufficient to produce a smaller particle size, however, as other ICS making the transition from CFC to HFA did not experience a change in particle size [1]. HFA-BDP and HFA-CIC each produce particle sizes in the 1.1 μm range, deposit >50% into the lower airways and distribute substantially to the small airways (<2 mm). Such small airways could only be reached previously using systemically administered therapy. The small airways are clearly involved in the pathophysiologic processes of asthma, thereby providing a rationale for the need for small-particle ICS. There remain questions, however, about how these new delivery characteristics will influence both the efficacy and safety of ICS. The advent of formulations with small particle sizes created new opportunities and challenges in understanding not only the relative benefits of the small-particle and large-particle ICS formulations, but also the relative risks. This review will focus on recent research that addressed those challenges in both the adult and pediatric populations with asthma. This review was based on a search of relevant articles using Pubmed.

Section snippets

Comparative trials with other ICS

A major advantage of small-particle ICS is that they have improved total lung deposition and consequently, effective asthma control is achieved at lower daily doses than the large-particle ICS. Several clinical trials demonstrated effective asthma control in patients with moderate to severe disease treated with half of the daily dose of HFA-BDP as compared with the dose of CFC-BDP [2]. A follow-up study showed that 12 months of treatment with HFA-BDP resulted in similar control of lung function

Local oropharyngeal adverse effects

Oropharyngeal adverse effects with CFC-ICS are uncommon, especially with spacer use and proper mouth rinsing. Small-particle inhalers generally deposit even lesser amounts of drug in the oropharynx (∼33%) than their CFC counterparts (∼82–91%), possibly resulting in a lower incidence of oropharyngeal candidiasis. Lipworth et al. [12] conducted a 12-week, placebo-controlled study in adults with mild to moderate asthma treated with HFA-CIC 320 μg qd, HFA-CIC 320 μg bid, or CFC-FP 440 μg bid. The

Summary

Compared to their older, large-particle counterparts, small-particle ICS have clearly resulted in a re-distribution of dose to the airways, with less deposition in the oropharynx, more deposition in the lungs, and more deposition in the periphery of the lungs. There does appear to be a resultant reduction in oropharyngeal candidiasis, thus improving local safety. However, there is little, if any, evidence to suggest that the change to small-particle ICS alone has improved efficacy or safety

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

References (24)

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