SFEBES2009 Poster Presentations Steroids (36 abstracts)
Modified-release hydrocortisone to provide circadian cortisol profiles
M Debono 1 , C Ghobadi 1 , A Rostami-Hodjegan 1 , H Huatan 2 , MJ Campbell 6 , J Newell-Price 1 , K Darzy 3 , DP Merke 4 , W Arlt 5 & RJ Ross 1
1Academic Units of Endocrinology & Clinical Pharmacology, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK; 2H2 Pharma, Sheffield, UK; 3East and North Hertfordshire NHS Trust, Howlands, Welwyn Garden City, UK; 4National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA; 5Section Endocrinology, Diabetes & Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK; 6Health Services Research ScHARR, University of Sheffield, Regent Court, 30 Regent street,
Sheffield, UK
Background: A basic tenet for hormone replacement is to replicate physiology but this is rarely if ever achieved. The adrenal glucocorticoid, cortisol, has a distinct circadian rhythm regulated by the brain’s central pacemaker. Loss of the cortisol circadian rhythm is associated with metabolic abnormalities, depression, fatigue and a poor health-related quality of life. Based on pharmacokinetic modelling we have developed a modified-release hydrocortisone (MR-HC) and tested whether it can reproduce physiological cortisol rhythms.
Methods: Using data from healthy reference subjects (n=33) we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release (IR-HC) in healthy volunteers (n=28). We compared profiles to physiological cortisol levels, and modelled an optimal treatment regimen.
Findings: We defined key variables in the physiological cortisol profile including: peak 400 nmol/l (95% reference range 296–540), acrophase 0832 h (95% CI 0759–0905 h), nadir <50 nmol/l (95% reference range 35–64), time of nadir 0018 h (95% CI 2339–0058 h), and quiescent phase (below the mesor) 1943 to 0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (S.E.M.) Cmax of 457 (38.4) nmol/l at 7.41 (0.57) hours after drug. Bioavailability of MR-HC 5, 10 & 15 mg was 100, 79, & 86% that of IR-HC. Modelling suggested that MR-HC 15 to 20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels.
Interpretation: By defining circadian rhythms and using modern formulation technology it is possible to generate physiological cortisol profiles. This approach provides a new paradigm for glucocorticoid replacement therapy with important clinical implications for the current management of adrenal insufficiency and congenital adrenal hyperplasia.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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