Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study

Background: Endogenous plasma cortisol levels have it well-defined circadian rhythm. The aim of this project is 10 develop a once daily oral dual-release Formulation For cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile. Objective: To determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets ill healthy Volunteers. In addition. the effect of food intake was investigated for the 20 mg dose. Design: A randomised, controlled. two-way cross-over. double-blind. phase I study of oral hydrocortisone (modified (dual) release: 5 and 20 mg) with all open food-interaction arm. Methods: The single dose pharmacokinetic studies were performed with betamethasone Suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in it fasting state. The third day was open with a 20 mg tablet taken 30 min after it high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC-MS/MS and an immunoassay The plasma pharmacokinetic variables were calculated using non-compartmental data analysis. Results: The time to reach it clinically significant plasma concentration of cortisol (> 200 nmol/l) Was within 20 min and a mean peak of 431 (S.D. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 It thereafter and all plasma concentrations 18-24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC-MS/MS and immunoassay. respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully Close proportional. Conclusion: The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.