title: Model-based covariate pharmacokinetic analysis and lack of cortisol suppression by the new inhaled corticosteroid ciclesonide using a novel cortisol release model.
abstract: 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 microg) 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 Emax 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.
authors.affiliation: Sanofi-Aventis, Bridgewater, New Jersey, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.forename: Marc
authors.initials: M
authors.lastname: Pfister
authors.forename: Srikumar
authors.initials: S
authors.lastname: Sahasranaman
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001249:Asthma / Q000188:drug therapy; D001835:Body Weight; D002648:Child; D002940:Circadian Rhythm; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D005006:Ethnicity; D005938:Glucocorticoids / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors*; D008168:Lung / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D011282:Pregnenediones / Q000009:adverse effects* / Q000378:metabolism* / Q000493:pharmacokinetics*; D011446:Prospective Studies; D012720:Severity of Illness Index; D012737:Sex Factors
chemical_list: D005938:Glucocorticoids; D011282:Pregnenediones; C494355:desisobutyrylciclesonide; C120481:ciclesonide; D006854:Hydrocortisone