M. Pfister, S. Krishnaswami, S. Rohatagi
Aventis Pharmaceuticals, Bridgewater, New Jersey
Objective: Ciclesonide (CIC) is a new inhaled glucocorticoid for the treatment of asthma that is converted into the active metabolite desisobutyryl-CIC (des-CIC) in the lungs. Study objectives were to characterize the circadian rhythm of endogenous cortisol release and to quantify the effect of systemic des-CIC concentrations on the endogenous cortisol release.
Methods: Demographic and pharmacokinetic/pharmacodynamic data from 12 Phase I and 3 Phase III studies in adults and 2 Phase III studies in pediatrics (ex-actuator dose: 40-2880 µg) were pooled for population analysis by NONMEM. Des-CIC concentrations were evaluated using one or two compartment models with appropriate covariates. Endogenous cortisol concentrations were characterized by various models such as the cosine model and a modified one-compartment model with first order elimination and first order input. 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 Emax model.
Results: There were 635 subjects in this analysis with 5238 and 4470 observations recorded for des-CIC and cortisol concentrations, respectively. A one-compartment model with first order absorption adequately described the des-CIC concentration–time profile. A simple one-compartment model with first order absorption, an endogenous “pre-dose” cortisol concentration at dose-interval and a lag-time based on a fixed, hypothetical cortisol dosing time of 10 PM could adequately characterize the circadian rhythm of endogenous cortisol release and was superior to other models such as the cosine model. The doses of CIC (up 1280 µg) and the AUC were not significant covariates for cortisol concentrations suggesting negligible effects on endogenous cortisol concentrations. Using an Emax model, an EC50 of des-CIC of 1.96 ng/mL was estimated. Less than 1% of all observed des-CIC concentrations are higher than the EC50, indicating a negligible effect of des-CIC on cortisol concentrations.
Conclusion: The novel one-compartment model adequately described the cortisol rhythm and des-CIC has a negligible effect on endogenous cortisol concentrations in adults and pediatrics at therapeutically relevant doses.
Reference: PAGE 13 (2004) Abstr 485 [www.page-meeting.org/?abstract=485]
Poster: poster