Chemical formula: C₃₂H₄₄O₇ Molecular mass: 540.697 g/mol PubChem compound: 6918155
Ciclesonide exhibits low binding affinity to the glucocorticoid-receptor. Once orally inhaled, ciclesonide is enzymatically converted in the lungs to the principal metabolite (C21-des-methylpropionyl-ciclesonide) which has a pronounced anti-inflammatory activity and is thus considered as the active metabolite.
In four clinical trials, ciclesonide has been shown to reduce airway hyperresponsiveness to adenosine monophosphate in hyperreactive patients with maximal effect observed at the dose of 640 micrograms. In another trial, pretreatment with ciclesonide for seven days significantly attenuated the early and late phase reactions following inhaled allergen challenge. Inhaled ciclesonide treatment was also shown to attenuate the increase in inflammatory cells (total eosinophils) and inflammatory mediators in induced sputum.
A controlled study compared 24-hour plasma cortisol AUC in 26 adult asthmatic patients following 7 days of treatment. Compared to placebo, treatment with ciclesonide 320, 640, and 1,280 micrograms/day did not statistically significantly lower the 24-hour time averages of plasma cortisol (AUC(0-24)/24 hours) nor was a dose-dependent effect seen.
In a clinical trial involving 164 adult male and female asthmatic patients, ciclesonide was given at doses of 320 micrograms or 640 micrograms/day over 12 weeks. After stimulation with 1 and 250 micrograms cosyntropin, no significant changes in plasma cortisol levels were observed versus placebo.
Double-blind placebo-controlled trials of 12-weeks duration in adults and adolescents have shown that treatment with ciclesonide resulted in improved lung function as measured by FEV1 and peak expiratory flow, improved asthma symptom control, and decreased need for inhaled beta-2 agonist.
In a 12-week study of 680 severe asthmatics, previously treated with 500-1,000 micrograms fluticasone propionate per day or equivalent, 87.3% and 93.3% of patients remained exacerbation-free during treatment with 160 or 640 micrograms of ciclesonide, respectively. At the end of the 12 week study period, the results showed a statistically significant difference between the doses of 160 micrograms and 640 micrograms/day ciclesonide with regard to the occurrence of an exacerbation after the first day of the study: 43 patients/339 (=12.7%) in the 160 micrograms/day group and 23 patients/341 (6.7%) in the 640 micrograms/day group (Hazard ratio=0.526; p=0.0134). Both ciclesonide doses resulted in comparable FEV1 values at 12 weeks. Treatment-related adverse events were seen in 3.8% and 5% of patients treated with 160 or 640 micrograms per day of ciclesonide respectively.
A further 52 week trial involving 367 patients with mild to moderate asthma,was unable to demonstrate a significant difference in the effect of higher doses of Ciclesonide (320 or 640 mcg per day) as compared to a lower dose (160 mcg per day) on asthma control.
Ciclesonide is presented in HFA-134a propellant and ethanol as a solution aerosol, which demonstrates a linear relationship between different doses, puff strengths and systemic exposure.
Studies with oral and intravenous dosing of radiolabeled ciclesonide have shown an incomplete extent of oral absorption (24.5%). The oral bioavailability of both ciclesonide and the active metabolite is negligible (<0.5% for ciclesonide, <1% for the metabolite). Based on a γ-scintigraphy experiment, lung deposition in healthy subjects is 52%. In line with this figure, the systemic bioavailability for the active metabolite is >50% by using the ciclesonide metered dose inhaler. As the oral bioavailability for the active metabolite is <1%, the swallowed portion of the inhaled ciclesonide does not contribute to systemic absorption.
Following intravenous administration to healthy subjects, the initial distribution phase for ciclesonide was rapid and consistent with its high lipophilicity. The volume of distribution averaged 2.9 l/kg. The total serum clearance of ciclesonide is high (average 2.0 l/h/kg) indicating a high hepatic extraction. The percentage of ciclesonide bound to human plasma proteins averaged 99%, and that of the active metabolite 98-99%, indicating an almost complete binding of circulating ciclesonide/active metabolite to plasma proteins.
Ciclesonide is primarily hydrolysed to its biologically active metabolite by esterase enzymes in the lung. Investigation of the enzymology of further metabolism by human liver microsomes showed that this compound is mainly metabolized to hydroxylated inactive metabolites by CYP3A4 catalysis. Furthermore, reversible lipophilic fatty acid ester conjugates of the active metabolite were detected in the lung.
Ciclesonide is predominantly excreted via the faeces (67%), after oral and intravenous administration, indicating that excretion via the bile is the major route of elimination.
Ciclesonide shows no pharmacokinetic changes in mild asthmatic patients compared to healthy subjects.
According to population pharmacokinetics, age has no impact on the systemic exposure of the active metabolite.
Reduced liver function may affect the elimination of corticosteroids. In a study including patients with hepatic impairment suffering from liver cirrhosis, a higher systemic exposure to the active metabolite was observed.
Due to the lack of renal excretion of the active metabolite, studies on renal impaired patients have not been performed.
Preclinical data with ciclesonide reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential.
In animal studies on reproductive toxicity, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal results do not seem to be relevant for humans given recommended doses.
A treatment-related effect on the ovaries (namely atrophy) was observed at the top dose in two 12-month studies in dogs. This effect occurred at systemic exposures 5.27-8.34 times those noted at the 160 µg daily dose. The relevance of this finding to humans is unknown.
Animal studies with other glucocorticoids indicate that administration of pharmacological doses of glucocorticoids during pregnancy may increase the risk for intrauterine growth retardation, adult cardiovascular and/or metabolic disease and/or permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour. The relevance of these data to humans administered ciclesonide by inhalation is unknown.
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