Anna Lönnebo1, Anders Grahnén, Mats O Karlsson. 1. Quintiles AB, Phase I Services, Uppsala and Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden. anna.lonnebo@quintiles.com
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 inhaledplacebo (Placebo Turbohaler) and 1600 microg 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 (IC(50) and A(50)) were 0.325 microg 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.
RCT Entities:
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 microg 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 (IC(50) and A(50)) were 0.325 microg 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.
Authors: H Möllmann; M Wagner; B Meibohm; G Hochhaus; J Barth; R Stöckmann; M Krieg; H Weisser; C Falcoz; H Derendorf Journal: Eur J Clin Pharmacol Date: 1998-02 Impact factor: 2.953
Authors: Rose T Faghih; Munther A Dahleh; Gail K Adler; Elizabeth B Klerman; Emery N Brown Journal: IEEE Trans Biomed Eng Date: 2015-04-29 Impact factor: 4.538
Authors: Ida Netterberg; Mats O Karlsson; Elisabet I Nielsen; Angelica L Quartino; Henrik Lindman; Lena E Friberg Journal: Br J Clin Pharmacol Date: 2018-01-18 Impact factor: 4.335