Improved glucocorticoid replacement therapy by a novel oral hydrocortisone modified-release tablet
Stanko Skrtic2, Hans Lennernäs3, Anna Nilsson1, Ragnhildur Bergthorsdottir1, Thomas Hedner2 & Gudmundur Johannsson1
Background: Mortality rate in patients with primary and secondary adrenal insufficiency is increased. A contributing factor could be the dose and the pattern of glucocorticoid replacement therapy. Hydrocortisone administered twice or thrice daily produces high serum peaks and low trough values in-between. A novel, once daily, hydrocortisone modified release tablet with combined immediate and extended release characteristics was developed.
Purpose: The aim was to determine single-dose pharmacokinetics and dose-proportionality of oral 5 and 20 mg modified-release hydrocortisone tablets in healthy volunteers.
Material and methods: Studies were performed with betamethasone suppression. The two first study days were blinded and randomized between the 5 and 20 mg tablet in a fasting state and the third was open with the 20 mg tablet taken 30 min after a high calorie, high fat meal. The plasma samples were assayed using a validated (GLP) LC-MS/MS method. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis.
Results and discussion: The time to reach a clinically significant serum concentration of cortisol (>200 nmol/L) was within 25 minutes and a peak of 400450 was obtained within 50 min after the 20 mg tablet. Serum cortisol levels remained above 200 nmol/L for around 6 h thereafter whereas all serum concentrations 1824 h after intake were below 50 nmol/L. In the fed state the time to 200 nmol/L was delayed by 4550 minutes. The 5 mg and 20 mg tablets produced almost superimposable profiles.
Conclusion: This modified-release tablet allows for a once-daily administration producing a near physiological serum cortisol profile. The time to clinically significant cortisol concentrations was short and after the peak level a slow decline occurred throughout the day allowing for a cortisol-free interval 1824 hour after intake. This new tablet for once-daily administration may help to improve compliance and outcome in patients with adrenal insufficiency.