Ciclesonide | place in therapy review Device Pressurized metered-dose inhaler Holding chamber, spacers Dry-powder inhalers Table 4 | Advantages and disadvantages of portable delivery devices for inhaled corticosteroids (Dolovich et al. 2005) Advantages No contamination Dose–dose reproducibility Some can be used with breath-actuated mouthpiece Decreased need for patient coordination Decreased pharyngeal deposition Less patient coordination required: breath actuated No propellant required Dose counters in most newer dosage forms Disadvantages Requires coordination and good technique High pharyngeal deposition Difficult to determine remaining dosage Added expense Less portable than metered-dose inhaler alone Dose delivered might be reduced Can deliver high pharyngeal deposition Moderate to high inspiratory flow required for actuation formulated in solution which in comparison with suspensions is likely to improve lung deposition characteristics (Berger 2005). In addition, other properties of ciclesonide and des-CIC, including low oral bioavailability (<1%), rapid systemic clearance and a high degree of plasma protein binding (99%) are designed to reduce the potential for systemic side effects. Therefore, the pharmacologic and pharmacokinetic characteristics of ciclesonide are intended to provide advancements in the treatment of asthma with a potentially improved safety profile. Systemic absorption In human lung tissue, a reversible lipid conjugation of des-CIC has been demonstrated. This may account for the prolonged antiinflammatory activity of inhaled ciclesonide in the lungs as this conjugated des-CIC may act as a reservoir (Berger 2005). The small particle size of ciclesonide improves its pulmonary deposition; studies have shown that up to 52% of an inhaled dose of ciclesonide is deposited in the small airways and alveoli following administration, and that the amount of deposition is not influenced by the use of a spacer device (Drollmann et al. 2006; Newman et al. 2006). The pharmacokinetics of ciclesonide and des-CIC are similar in healthy subjects and in patients with asthma, confirming that airway activation of the drug is unimpaired by the disease (Nave et al. 2006). Compared with fluticasone and budesonide, smaller amounts of ciclesonide are available for systemic absorption through the gastrointestinal tract as lower amounts are deposited in the mouth and oropharynx. In a study of adults with bronchial asthma, the oropharyngeal deposition of ciclesonide was about 50% of that reported with fluticasone propionate, with 90% less des-CIC present in the oropharyngeal cavity compared with fluticasone following inhalation (Richter et al. 2005). Following administration of ciclesonide and budesonide to healthy volunteers, the maximal concentrations of ciclesonide and des-CIC recovered from oropharyngeal wash were 30% and 0.67% of budesonide, respectively (Nave et al. 2005a). Ciclesonide and budesonide concentrations in the wash decreased rapidly within 15 min of administration. The concentrations of des-CIC in the oropharynx 60 238 min after inhalation were only 4% of the budesonide concentration (Nave et al. 2005a), and 8% of the fluticasone concentration (Richter et al. 2005). Ciclesonide undergoes first-pass hepatic inactivation (>99%) following oral administration, rendering systemic bioavailability from the oral route essentially negligible (Nave et al. 2004). Furthermore, there is a low potential for adverse systemic side effects with inhaled ciclesonide as it is highly protein bound (>99%) and a low fraction of unbound active metabolite is available in the systemic circulation (Rohatagi et al. 2005). The unbound fraction is also rapidly cleared further limiting systemic availability (Berger 2005). Pulmonary function Laboratory measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF) provide a direct, objective measure of treatment effect on airflow limitation in asthma. Use of a spirometer to assess FEV1 and FVC is helpful for diagnosing and monitoring the progress of asthma and response to therapy. Measurement of PEF with a peak expiratory flow meter can provide additional asthma monitoring information. However, PEF measures are not interchangeable with FEV1 and FVC, and do not always correlate with asthma severity; the relationship between FEV1 and PEF and asthma severity, airway inflammation, and HRQOL is complex and not well established. Initial phase II studies documented a decrease in airway hyperresponsiveness after adenosine monophosphate (AMP) challenges with ciclesonide therapy; efficacy was similar to that of both fluticasone and budesonide (Taylor et al. 1999; Kanniess et al. 2001; Lee et al. 2004; Derom et al. 2005). In placebo-controlled trials, ciclesonide demonstrated improvements in pulmonary function over a range of doses in patients with asthma with varying degrees of severity from mild to severe (Table 5). Single daily ciclesonide doses of at least 80 mcg daily were associated with significant improvements from baseline in pulmonary function compared with placebo (Langdon et al. 2005). Studies comparing single daily ciclesonide doses of 800 and 1600 mcg have not demonstrated superiority of the higher dose regimen (Chapman et al. 2002; O'Connor et al. © 2006 Core Medical Publishing Limited