Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles
- 1 May 2009
- journal article
- research article
- Published by The Endocrine Society in Journal of Clinical Endocrinology & Metabolism
- Vol. 94 (5), 1548-1554
- https://doi.org/10.1210/jc.2008-2380
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.Keywords
This publication has 33 references indexed in Scilit:
- Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiencyClinical Endocrinology, 2008
- Modified‐release hydrocortisone for circadian therapy: a proof‐of‐principle study in dexamethasone‐suppressed normal volunteersClinical Endocrinology, 2007
- Continuous subcutaneous hydrocortisone infusion in Addison’s diseaseActa Endocrinologica, 2007
- Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasiaClinical Endocrinology, 2006
- Why is the management of glucocorticoid deficiency still controversial: a review of the literatureClinical Endocrinology, 2005
- Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed restJournal of Applied Physiology, 2004
- Adrenal insufficiencyThe Lancet, 2003
- Resetting of Circadian Time in Peripheral Tissues by Glucocorticoid SignalingScience, 2000
- Impact of sleep debt on metabolic and endocrine functionThe Lancet, 1999
- ENDOCRINE FUNCTIONS IN YOUNG MEN EXPOSED FOR ONE NIGHT TO A 50-HZ MAGNETIC FIELD. A CIRCADIAN STUDY OF PITUITARY, THYROID AND ADRENOCORTICAL HORMONESLife Sciences, 1997