| 1. |
- Lönnebo, Anna, et al.
(författare)
-
An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers
- 2007
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 64:2, s. 125-132
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: Budesonide, a glucocorticosteroid, is used as a first-line treatment for asthma. The aim of the study was to develop a PK/PD model for the effect of budesonide on ACTH and cortisol. Methods: The modelling data were generated by conducting a single-blind, randomized, placebo-controlled cross-over study. Ten healthy volunteers inhaled placebo (Placebo Turbohaler) and 1600 μg budesonide (Pulmicort Turbohaler), with a wash-out period of 7 days between treatments. Baseline concentrations of cortisol and ACTH were measured after placebo treatment and concentrations of cortisol, ACTH and budesonide were assessed after budesonide treatment. A one-compartment disposition model was used for budesonide disposition. Based on indirect response models, two types of models, distinguishing between production driven by a sum of cosine functions and production driven by surges, were used in parallel to describe the data. Results: The surge-based approach was the most appropriate, based on goodness-of-fit, objective function values and number of parameters. The surge-based model that integrated both ACTH and cortisol data was chosen as the final model. The estimated half-lives of endogenous ACTH and cortisol were 9 and 113 min, respectively. The budesonide and ACTH concentrations producing 50% of the maximal response (IC50 and A50) were 0.325 μg l-1 and 4.96 pmol l-1. Conclusions: The present PK/PD model of the effect of budesonide on ACTH and cortisol can serve as a tool for further understanding of the hypothalamic-pituitary-adrenal (HPA) axis and be useful in the development of drugs interacting with the axis.
|
|
