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Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles

Academic Unit of Diabetes (M.D., J.N.-P., R.J.R.), Endocrinology and Reproduction, and Academic Unit of Clinical Pharmacology (C.G., A.R.-H.), School of Medicine, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, United Kingdom; H2Pharma Consulting Limited (H.H.), Kent ME14 5FR, United Kingdom; Health Services Research Sheffield School of Health and Related Research (M.J.C.), University of Sheffield, Sheffield S1 4DA, United Kingdom; Diabetes and Endocrinology (K.D.), East and North Hertfordshire National Health Service Trust, Howlands, Welwyn Garden City AL7 4HQ, United Kingdom; National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892-1932; and Centre for Endocrinology, Diabetes and Metabolism (W.A.), School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom

Address all correspondence and requests for reprints to: Professor Richard J. M. Ross, University of Sheffield, Room 112 Floor M, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom. E-mail: r.j.ross{at}sheffield.ac.uk.

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.

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