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An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers
Author(s) -
Lönnebo Anna,
Grahnén Anders,
Karlsson Mats O.
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02867.x
Subject(s) - budesonide , placebo , glucocorticoid , hydrocortisone , corticosteroid , medicine , adrenocorticotropic hormone , asthma , endocrinology , cortisol awakening response , hormone , alternative medicine , pathology
What is already known about this subject • The functionality of the HPA axis through cortisol production has been the subject for several investigations. • Modelling of cortisol production has been described by endogenous substance models utilizing a combination of indirect response functions and sum of cosine functions. • The effect of glucocorticoid drugs on cortisol production has been investigated using these models. What this study adds • Previous investigations (models) have not primarily considered the combined action of ACTH and cortisol. • Since ACTH drives cortisol production we adopted, for our modelling, the same approach as previous investigations but we distinguished between two types of models for the production of cortisol (driven by ACTH), one being the sum of cosine functions, the other being described by surges. • The presented surge‐based model can serve as a tool for further understanding of the HPA axis and may also prove useful in the development of drugs interacting with the axis. 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 (I C 50 and A 50 ) 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.