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Modified-release hydrocortisone to provide circadian cortisol profiles

Debono, M., Ghobadi, C., Rostami-Hodjegan, A., Huatan, H., Campbell, M.J., Newell-Price, J., Darzy, K., Merke, D.P., Arlt, W. and Ross, R.J. (2009) Modified-release hydrocortisone to provide circadian cortisol profiles. Journal of Clinical Endocrinology and Metabolism, 94 (5). pp. 1548-1554. ISSN 0021-972X

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Context: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles.

Setting: The study was performed at a Clinical Research Facility.

Design and Methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen.

Results: The key variables in the physiological cortisol profile included: peak 15.5 mu g/dl (95% reference range 11.7-20.6), acrophase 0832 h(95% confidence interval 0759-0905), nadir less than 2 mu g/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (SEM) maximum observed concentration of 16.6 (1.4) mu g/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels.

Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. (J Clin Endocrinol Metab 94: 1548-1554, 2009)

Item Type: Article
Copyright, Publisher and Additional Information: © 2009 Endocrine Society. This is an author produced version of a paper subsequently published in Journal of Clinical Endocrinology and Metabolism. Uploaded in accordance with the publisher's self-archiving policy.
Keywords: hydrocortisone, modified-release, adrenal insufficiency, circadian
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Health and Related Research (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 19 Jun 2009 11:35
Last Modified: 08 Feb 2013 16:58
Published Version: http://dx.doi.org/10.1210/jc.2008-2380
Status: Published
Publisher: Endocrine Society
Refereed: Yes
Identification Number: 10.1210/jc.2008-2380
URI: http://eprints.whiterose.ac.uk/id/eprint/8641

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