Modified-release hydrocortisone to provide circadian cortisol profiles
Author(s)
Type
Journal Article
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.
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 μg/dl (95% reference range 11.7–20.6), acrophase 0832 h (95% confidence interval 0759–0905), nadir less than 2 μg/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) μg/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.
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 μg/dl (95% reference range 11.7–20.6), acrophase 0832 h (95% confidence interval 0759–0905), nadir less than 2 μg/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) μg/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.
Date Issued
2009-05-01
Date Acceptance
2009-02-09
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2009, 94 (5), pp.1548-1554
ISSN
0021-972X
Publisher
Oxford University Press
Start Page
1548
End Page
1554
Journal / Book Title
Journal of Clinical Endocrinology and Metabolism (JCEM)
Volume
94
Issue
5
Copyright Statement
Copyright © 2009 by The Endocrine Society.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/19223520
PII: jc.2008-2380
Subjects
ADDISONS-DISEASE
ADRENAL INSUFFICIENCY
Endocrinology & Metabolism
HORMONES
Life Sciences & Biomedicine
MELATONIN
PITUITARY
PLASMA-CORTISOL
PREMATURE MORTALITY
RHYTHMS
Science & Technology
SERUM CORTISOL
SUBJECTIVE HEALTH-STATUS
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2009-02-17