Ciclesonide: a novel inhaled corticosteroid for asthma

Abstract

The adoption of inhaled corticosteroids for the treatment of asthma has resulted in significant improvements in asthma symptoms and pulmonary function, and has reduced the incidence of asthma exacerbations, emergency room visits and hospitalizations. Although inhaled corticosteroids are generally safe and well tolerated compared with oral corticosteroids, concerns remain about potential side effects. Clinically significant complications include local effects such as dysphonia and oral candidiasis and potentially serious systemic effects associated with cortisol suppression including growth retardation, glucose intolerance and increased risk for osteoporosis and fractures. These side effects are more likely to occur with long-term use and are dose related. Over the years, attempts have been made to develop corticosteroids with potent local antiinflammatory activity and an improved safety profile. Ciclesonide ([R]-11 beta,16 alpha,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with cyclohexanecarboxaldehyde 21-isobutyrate) was designed to achieve these objectives. Ciclesonide is a parent compound that is converted locally in airways by esterases to produce the active metabolite, desisobutyryl-ciclesonide (des-CIC). The active metabolite, des-CIC, has a 100-fold greater relative glucocorticoid receptor binding affinity than ciclesonide itself (relative glucocorticoid receptor binding affinities are 1200 and 12, respectively; dexamethasone reference is 100). If any ciclesonide enters the circulation, it is highly protein bound (99%) and extensively metabolized by liver oxidases, resulting in very low systemic exposure. Ciclesonide is delivered in solution form via a hydrofluoroalkane metered-dose inhaler (MDI) with a once-daily dosing schedule, which facilitates patient compliance. Clinical studies demonstrate that ciclesonide is as effective as existing "gold standard" inhaled corticosteroids for control of asthma and has a good safety profile.