Pharmacodynamic properties
Ciclesonide is a prodrug which is enzymatically converted to the pharmacologically active metabolite desisobutyryl-ciclesonide (des-ciclesonide) following inhalation. The glucocorticoid-receptor affinity of des-ciclesonide was tested in rats and humans and demonstrated that the glucocorticoid-receptor affinity of des-ciclesonide is up to 120 times greater than the parent compound’s affinity and 12 times greater than dexamethasone’s affinity. Des-ciclesonide has anti-inflammatory properties which are exerted through a wide range of inhibitory activities.
In general, cortisol levels serve as a marker for suppression of the hypothalamic-pituitary-adrenal axis by systemic action of corticosteroids which could be associated with side effects.
No statistically significant suppression of cortisol levels was observed in horses with equine asthma at the recommended dosing regimen and in healthy horses with ciclesonide treatment up to three times the dose and three times the duration.
The pivotal field trial included horses (mean age 18.5 years) with severe equine asthma characterised by the following main criteria: clinical signs >14 days duration; horses that tolerated insertion of the nostril adapter; laboured breathing at rest; weighted clinical score ≥11/23. The weighted clinical score included the following parameters: coughing, nasal discharge, nasal flaring, laboured breathing at rest, respiratory rate, tracheal sounds and abnormal lung sounds. Clinical success was defined as an improvement of at least 30% in the weighted clinical score. In total, 73.4% of the ciclesonide group and 43.2% of the placebo group demonstrated treatment success, and the difference between the groups was statistically significant.
Pharmacokinetic particulars
Absorption: Ciclesonide was rapidly absorbed after inhalation with a median Tmax of about 5 minutes after the last actuation and rapidly converted to its active metabolite des-ciclesonide as shown by concentrations at the first sampling time, i.e. 5 minutes after the last actuation.
Distribution: The volume of distribution in horses is 25.7 l/kg, indicating that ciclesonide is distributed readily into the tissues. Following inhalative administration in horses, the absolute systemic bioavailability of ciclesonide was very low and was not higher than 5%-17%. The apparent systemic bioavailability of des-ciclesonide following administration of ciclesonide was in the range of 33.8%-59.0%. The plasma exposure for ciclesonide and des-ciclesonide in terms of Cmax and AUClast increased with the dose. A slight trend to an increase of plasma exposure higher than the dose proportionality was observed. In-vitro protein binding of des -ciclesonide was tested in the plasma from mice, rats, rabbits, dogs and humans (mouse plasma 98.9% to 99.1%; rat plasma 97.5% to 98.0%; rabbit plasma 99.1% to 99.2%; dog plasma 97.9% to 98.0%; human plasma 98.5% to 98.8%).
Metabolism: Ciclesonide is a pro-drug that is rapidly metabolized to the major active metabolite (des-ciclesonide) after inhalation. In vitro, three metabolites were reported as major metabolites. In vivo, only des-ciclesonide occurred whereas the other two metabolites could not be confirmed.
Elimination: The mean apparent harmonic terminal half-life after single inhalation administration was approximately 3-5 hours for ciclesonide and approximately 4-5 hours for des-ciclesonide. Elimination of ciclesonide and its active metabolite des-ciclesonide is principally via faeces.