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Modified-release hydrocortisone to provide circadian cortisol profiles.

Modified-release hydrocortisone to provide circadian cortisol profiles.

Authors :
Debono M
Ghobadi C
Rostami-Hodjegan A
Huatan H
Campbell MJ
Newell-Price J
Darzy K
Merke DP
Arlt W
Ross RJ
Source :
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2009 May; Vol. 94 (5), pp. 1548-54. Date of Electronic Publication: 2009 Feb 17.
Publication Year :
2009

Abstract

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.<br />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.<br />Setting: The study was performed at a Clinical Research Facility.<br />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.<br />Results: The key variables in the physiological cortisol profile included: peak 15.5 microg/dl (95% reference range 11.7-20.6), acrophase 0832 h (95% confidence interval 0759-0905), nadir less than 2 microg/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) microg/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.<br />Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.

Details

Language :
English
ISSN :
1945-7197
Volume :
94
Issue :
5
Database :
MEDLINE
Journal :
The Journal of clinical endocrinology and metabolism
Publication Type :
Academic Journal
Accession number :
19223520
Full Text :
https://doi.org/10.1210/jc.2008-2380