A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (ChronocortTM) vs. conventional hydrocortisone (CortefTM) in the treatment of congenital adrenal hyperplasia

• Published in: Clinical endocrinology (Oxford) Vol. 72; no. 4; pp. 441 - 447
• Main Authors: Verma, Somya, VanRyzin, Carol, Sinaii, Ninet, Kim, Mimi S., Nieman, Lynnette K., Ravindran, Shayna, Calis, Karim A., Arlt, Wiebke, Ross, Richard J., Merke, Deborah P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2010; Blackwell; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adrenal Hyperplasia, Congenital - drug therapy; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adult; Area Under Curve; Biological and medical sciences; Circadian Rhythm; Cross-Over Studies; Delayed-Action Preparations - pharmacokinetics; Delayed-Action Preparations - therapeutic use; Drug Administration Schedule; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Humans; Hydrocortisone - administration & dosage; Hydrocortisone - pharmacokinetics; Male; Medical sciences; Middle Aged; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Vertebrates: endocrinology; Endocrinopathy; Corticosteroid; Pharmacodynamics; Adrenal cortex diseases; Steroid hormone; Controlled release form; Antiinflammatory agent; Hyperadrenocorticism; Hydrocortisone; Enzymopathy; Glucocorticoid; Biological activity; Congenital adrenal hyperplasia syndrome; Treatment; Adrenal hormone; Adrenal gland diseases; Pharmacokinetics; Endocrinology; Comparative study
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2009.03636.x

Summary
Objective  Existing glucocorticoid treatment for congenital adrenal hyperplasia (CAH) is suboptimal and nonphysiological. We compared hormonal profiles during therapy with a new modified‐release hydrocortisone (MR‐HC), Chronocort™, to conventional hydrocortisone (HC), Cortef™, in patients with CAH.
Design and patients  We conducted a Phase 2, open‐label, crossover pharmacokinetic and pharmacodynamic study in 14 patients (out of whom seven were male subjects, age ranging from 17 to 55) with classic 21‐hydroxylase deficiency. One week of thrice daily HC (10, 5 and 15 mg) was followed by 1 month of once daily MR‐HC (30 mg at 22:00 hours). Twenty four‐hour sampling of cortisol, 17‐hydroxyprogesterone (17‐OHP), androstenedione, and ACTH was performed at steady state.
Measurements  The primary outcome measures were 8‐ and 24‐h area under the curve (AUC) hormones and 08:00 hours 17‐OHP.
Results  Hydrocortisone therapy resulted in three cortisol peaks. A single cortisol peak occurred at approximately 06:00 hours on MR‐HC. MR‐HC resulted in significantly (P < 0·001) lower 24‐h afternoon (12:00 to 20:00 hours), and night‐time (20:00 to 04:00 hours) cortisol as compared with HC. From 04:00 to 12:00 hours, when physiological cortisol is highest, cortisol was higher on MR‐HC than HC (P < 0·001). Patients on MR‐HC had significantly (P < 0·05) higher afternoon (12:00 to 20:00 hours) 17‐OHP, androstenedione and ACTH, but significantly (P = 0·025) lower 08:00 hours 17‐OHP. No serious adverse events occurred.
Conclusions  Modified‐release hydrocortisone represents a promising new treatment for CAH. Overnight adrenal androgens were well‐controlled, but rose in the afternoon with once‐daily dosing suggesting that a morning dose of glucocorticoid is needed. Further studies are needed to determine the optimal dosing regimen and long‐term clinical outcome.