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

Abstract

Background: Endogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to 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 in 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 an 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 a fasting state. The third day was open with a 20 mg tablet taken 30 min after a highcalorie, 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 a clinically significant plasma concentration of cortisol (O200 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 h 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 dose proportional. Conclusion: The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.

Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison’s disease

“…In particular, a dual-release preparation of hydrocortisone (Plenadren) was developed to maintain cortisol levels in a more physiological range, as clearly demonstrated in a phase I study [21].…”

Review: Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy

“…In a study to determine single dose pharmacokinetics and dose proportionality it was shown that the time to reach a serum concentration of cortisol (>200 nmol/l) of clinical significance was within 25 minutes and a peak of 400450 nmol/l was obtained within 50 minutes after the 20 mg tablet. Serum cortisol persisted above 200 nmol/l for around 6 h thereafter whereas all serum concentrations 1824 h after intake were below 50 nmol/l [Johannsson et al 2009]. This formulation was unable to fully replicate the physiological cortisol rhythm as taking the tablet at 07:00 misses the 03:00 cortisol rise.…”

Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency

“…One reason for impaired subjective health may be that common replacement regimens are not able to mimic the physiological diurnal pattern of cortisol secretion (1). This might be overcome by promising new developments of time-released medication (17,18). In addition, subjective health may also be affected by multiple aspects of SAI such as the mere fact of having a chronic disease, the need for chronic medication, or working disability (7,19).…”