An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers
2007 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 64, no 2, 125-132 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 64, no 2, 125-132 p.
ACTH, Circadian variation, Cortisol, HPA axis, Modelling, Population pharmacokinetics-pharmacodynamics
IdentifiersURN: urn:nbn:se:uu:diva-13727DOI: 10.1111/j.1365-2125.2007.02867.xISI: 000248512200003PubMedID: 17335542OAI: oai:DiVA.org:uu-13727DiVA: diva2:41497