Population pharmacokinetics and pharmacodynamics of ciclesonide

被引:92
作者
Rohatagi, S
Arya, V
Zech, K
Nave, R
Hochhaus, G
Jensen, BK
Barrett, JS
机构
[1] Aventis Pharmaceut, Bridgewater, NJ 08807 USA
[2] ALTANA Pharma, Constance, Germany
[3] Univ Florida, Gainesville, FL 32611 USA
关键词
ciclesonide; CIC-AP; corticosteroids; asthma therapy;
D O I
10.1177/0091270002250998
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Ciclesonide is a novel glucocorticoid that is converted into ciclesonide-active principle (CIC-AP) in the lung. The study objectives were to identify a structural model for population pharmacokinetic (PK) analysis of CIC-AP using nonlinear mixed-effects modeling, assess the influence of select covariates on PK and/or pharmacodynamic (PD)parameters, and investigate the effects of CIC-AP on endogenous cortisol. Pooled concentration data from nine phase I studies (dose: 400-3600 mug) involving healthy and asthmatic patients were included in the PK analysis. There were 151 subjects (3300 observations) for the CIC-AP population PK analysis. Various models examined inter- and intrasubject variability for the PK parameters. Population estimates of the PK parameters of clearance and volume of distribution were 396 L/h (64.8% co-efficient of variation [CV]) and 1190 L (41.2% CV), respectively. Pharmacodynamic population estimates included maximum cortisol release rate, 3140 ng/h (5.4% CV). The EC50 of CIC-AP was 0.88 ng/mL. Ciclesonide is a safe corticosteroid that causes negligible cortisol suppression. The disposition and effect of CIC-AP can be described using mixed-effect modeling. The estimated EC50 is similar to mean C-max from an 800-mug dose, further suggesting CIC-AP has little effect on cortisol suppression.
引用
收藏
页码:365 / 378
页数:14
相关论文
共 31 条
[1]  
BETHKE TD, 2002, EUR RESPIR J, V20, pP1914
[2]  
BOECKMANN AJ, 1994, NONMEM USERS GUIDE, V1
[3]   Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy - 2. Review of the literature [J].
Chrousos, GP ;
Harris, AG .
NEUROIMMUNOMODULATION, 1998, 5 (06) :288-308
[4]   Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients [J].
Clark, DJ ;
Grove, A ;
Cargill, RI ;
Lipworth, BJ .
THORAX, 1996, 51 (03) :262-266
[5]   Pharmacokinetics and pharmacodynamics of inhaled corticosteroids [J].
Derendorf, H ;
Hochhaus, G ;
Meibohm, B ;
Möllmann, H ;
Barth, J .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1998, 101 (04) :S440-S446
[6]  
DEROM E, 2001, EUR RESP J S33, V18, pA1015
[7]   Effects of budesonide and fluticasone on 24-hour plasma cortisol - A dose-response [J].
Donnelly, R ;
Williams, KM ;
Baker, AB ;
Badcock, CA ;
Day, RO ;
Seale, JP .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 156 (06) :1746-1751
[8]  
DROLLMAN A, 2002, EUR RESPIR J, V20, pP1914
[9]  
DROLLMAN A, 2001, EUR RESP J S33, V18, pP680
[10]   Comparing non-hierarchical models: Application to non-linear mixed effects modeling [J].
Ette, EI .
COMPUTERS IN BIOLOGY AND MEDICINE, 1996, 26 (06) :505-512