Modified-release hydrocortisone to provide circadian cortisol profiles

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: ...