Model-based Covariate Pharmacokinetic Analysis and Lack of Cortisol Suppression by the New Inhaled Corticosteroid Ciclesonide Using a Novel Cortisol Release Model

Ciclesonide is a novel and effective inhaled corticosteroid for the treatment of asthma that is converted into the active metabolite C21-desisobutyryl-ciclesonide (des-CIC) in the lung. The objectives of this analysis were to characterize covariate effects on des-CIC pharmacokinetics (PK) and circadian cortisol release. In addition, the effect of systemic des-CIC exposure on circadian cortisol release was also evaluated. Data from 12 phase I and 3 phase III studies in adults and 2 phase III studies in children (ex-actuator dose of ciclesonide: 40-2880 µg) were pooled. There were 635 subjects in the analysis with 5238 and 4470 observations recorded for concentrations of des-CIC and cortisol, respectively. The des-CIC PK was described using a 1-compartment model with first-order absorption and no clinically relevant differences in des-CIC PK due to body weight, race, asthma severity, or gender. The mean PK parameters estimates of apparent clearance and apparent volume of distribution were 302 L/h and 1310 L, respectively. A 1-compartment model with first-order absorption, an endogenous “predose” cortisol concentration at dose interval and a lag time based on a fixed, hypothetical cortisol dosing time of 10:00 PM could adequately characterize the circadian rhythm of endogenous cortisol release. The potential effect of des-CIC on the circadian rhythm of endogenous cortisol release was evaluated using dose and AUC as covariates and applying the E_max model. Less than 1% of all observed des-CIC concentrations were higher than the EC₅₀ for cortisol suppression, indicating negligible changes in cortisol concentrations at therapeutically relevant doses.