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An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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
Abstract [en]

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.
Keyword [en]
ACTH, Circadian variation, Cortisol, HPA axis, Modelling, Population pharmacokinetics-pharmacodynamics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-13727DOI: 10.1111/j.1365-2125.2007.02867.xISI: 000248512200003PubMedID: 17335542OAI: oai:DiVA.org:uu-13727DiVA: diva2:41497
Available from: 2008-01-25 Created: 2008-01-25 Last updated: 2018-01-12Bibliographically approved

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Grahnén, AndersKarlsson, Mats O.

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