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

• Published in: European journal of endocrinology Vol. 161; no. 1; pp. 119 - 130
• Main Authors: Johannsson, Gudmundur, Bergthorsdottir, Ragnhildur, Nilsson, Anna G, Lennernas, Hans, Hedner, Thomas, Skrtic, Stanko
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.07.2009
• Subjects: Administration; administration & dosage; Administration, Oral; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - blood; Anti-Inflammatory Agents - pharmacokinetics; Biological and medical sciences; blood; Circadian Rhythm; Clinical Study; Cross-Over Studies; Eating; Endocrinopathies; FARMACI; Female; Fundamental and applied biological sciences. Psychology; Hormone Replacement Therapy; Hormone Replacement Therapy - methods; Humans; Hydrocortisone; Hydrocortisone - administration & dosage; Hydrocortisone - blood; Hydrocortisone - pharmacokinetics; Male; MEDICAL AND HEALTH SCIENCES; Medical sciences; MEDICIN; MEDICIN OCH HÄLSOVETENSKAP; MEDICINE; methods; Middle Aged; Oral; pharmacokinetics; PHARMACY; Tablets; Vertebrates: endocrinology; Young Adult; Corticosteroid; Replacement therapy; Steroid hormone; Controlled release form; Antiinflammatory agent; Hydrocortisone; Glucocorticoid; Improvement; Adrenal hormone; Dosage form; Tablet; Pharmacokinetics; Endocrinology
• ISSN: 0804-4643; 1479-683X; 1479-683X
• DOI: 10.1530/EJE-09-0170

BackgroundEndogenous 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.ObjectiveTo 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.DesignA 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.MethodsThe 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 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.ResultsThe time to reach a 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 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.ConclusionThe dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.