Endocrine Abstracts

Replication of physiology is a basic tenet of endocrinology but this is rarely achieved. We developed a modified-release hydrocortisone to provide circadian cortisol. The adrenal glucocorticoid, cortisol, is an essential stress hormone and its secretion follows a distinct rhythm regulated by the central circadian oscillator in the suprachiasmatic nucleus. Circulating cortisol levels are low at sleep onset, rise between 0200 and 0400 h, peak within an hour of waking and then decline through the day. Loss of this rhythm, as occurs in adrenal insufficiency, is associated with metabolic abnormalities, fatigue and poor quality of life, despite replacement with immediate release hydrocortisone. Our aim was to investigate whether an oral formulation of modified release hydrocortisone (Chronocort) could replicate the physiological cortisol rhythm in normal healthy volunteers. Using reference subjects (n=33) we defined the normal cortisol rhythm. We then tested Chronocort against immediate-release (IR-HC) in dexamethasone suppressed healthy volunteers (n=28). Chronocort 15mg demonstrated delayed and sustained release: mean (S.E.M.) C_max 457 (38·4) nmol/l at 7·41 (0·57) hrs after drug. Bioavailability of Chronocort 5, 10, 15 & 30 mg was 100, 79, 86, & 69% that of IR-HC. In patients with CAH, Chronocort 30 mg, showed a similar pharmacokinetic profile to that seen in healthy volunteers and controlled early morning (0800 h) ACTH and 17OH-progesterone. Modelling demonstrated that Chronocort 15 to 20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. In conclusion, 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 congenital adrenal hyperplasia and adrenal insufficiency.