Table 3 | Pharmacokinetic profiles of currently available inhaled corticosteroids (Reynolds & Scott 2004; Anon. 2005a; Hübner et al. 2005; Wickersham & Novak 2005) Lung deposition (MDI-HFA) (%) Oral bioavailabilitya (%) Protein binding (%) Metabolism Excretion Suggested dosing frequency 11–32 26 <1 7 <1 11 21.5 87 88 99 80 90 98–99 71 Drug Beclomethasone propionate Budesonide Ciclesonide Flunisolide Fluticasone propionate Mometasone furoate – Triamcinolone acetonide 51b 28 52 39 16 22b aDepends on the delivery device used. bDelivery device not specified. MDI-HFA, metered-dose inhaler with hydrofluoroalkane propellant. and decreased osteoblast activity have been reported with high- dose inhaled corticosteroid therapy, the clinical significance of these effects is controversial. Additionally, patients receiving high doses of inhaled corticosteroids may be exposed to intermittent courses of systemic glucocorticoids that complicate the assessment of the impact of high-dose inhaled corticosteroid treatment alone (Anon. 2005b). Of the available inhaled corticosteroids, comparative studies have shown that budesonide, mometasone, and fluticasone have a lower potential to cause systemic effects as compared with beclomethasone dipropionate and triamcinolone (Crim et al. 2001; Anon. 2005b). Ideally, once a patient’s symptoms are controlled, the dose of inhaled corticosteroid should be reduced to the minimum effective dose to promote safe and cost-effective asthma control (British Thoracic Society 2005). Unfortunately, this approach is not always undertaken and patients are not infrequently exposed to unnecessarily high doses and an increased risk of adverse effects (O'Connell 2005). Beyond the specific drug selected, the device used to deliver the therapeutic entity can have a profound effect on treatment outcome. In an attempt to maximize drug delivery to the lungs, a variety of inhaler devices have been developed. The device also impacts the efficacy of therapy and has associated advantages and disadvantages (Table 4). The delivery device as well as the specific drug evaluated and the dose selected must all be considered when evidence of inhaled corticosteroid efficacy and adverse effects are taken into account. Environmental concerns have mandated alternatives to the use of chlorofluorocarbon (CFC) propellants in metered-dose inhalers. The change to hydrofluoroalkane propellants has resulted in some products that have different characteristics from previous formulations (Dolovich et al. 2005). Therefore, interpretation of reported efficacy and adverse effect data also requires an understanding of the propellant used. Core Evidence 2006;1(4) Ciclesonide | place in therapy review Hepatic Hepatic Hepatic Hepatic Hepatic Hepatic Mostly hepatic, some renal Feces, urine (<10%) Twice daily Urine (60%), feces Feces (77.9%) Once or twice dailya Once daily Renal (50%), feces (40%) Twice daily Feces (urine <0.02%) Twice daily Feces (74%), urine (8%) Once or twice daily Urine (40%), feces (60%) Twice daily Even at low daily doses, local adverse effects (dysphonia, oral candidiasis, and pharyngitis) to inhaled corticosteroids are reported at widely varying rates (5–58%) (Roland et al. 2004). The reported prevalence of these local effects is influenced by the type of study, length of observation, delivery device used, and method for recording (questionnaire or clinical examination). Local adverse effects may complicate treatment and lead to a disruption of therapy and worsening of disease. Despite advances in delivery device and drug development, there is still a need for inhaled corticosteroid therapies that are highly specific to the site of action, the lungs, with minimal systemic absorption. Ciclesonide was developed in response to this need. Clinical evidence with ciclesonide in asthma Level 2 evidence from fully published studies investigating the efficacy and safety of ciclesonide is available, including placebo- controlled studies (Chapman et al. 2005; Langdon et al. 2005; Pearlman et al. 2005; Bateman et al. 2006b; Gelfand et al. 2006) and trials with active comparator (Buhl et al. 2005a; Niphadkar et al. 2005; Boulet et al. 2006a; Hansel et al. 2006). Further evidence is also currently available in abstract form only, hindering full critical appraisal. Outcomes studied include disease-oriented measurable endpoints of respiratory function, inflammatory markers, and HPA suppression, as well as patient-oriented outcomes such as asthma symptoms, health-related quality of life (HRQOL), and use of rescue medication. Comparator drug propellant is not consistently reported which makes an assessment of delivery device difficult. Ciclesonide is a prodrug whereas the other inhaled corticosteroids are delivered to the site of action in their active form. Ciclesonide is converted to its active and highly potent metabolite, des-CIC, by esterases in the airways, thus providing active drug at the intended site of action. Ciclesonide is also 237