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A pharmacokinetic and pharmacodynamic study of delayed‐ and extended‐release hydrocortisone (Chronocort TM ) vs. conventional hydrocortisone (Cortef TM ) in the treatment of congenital adrenal hyperplasia
Author(s) -
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.
Publication year - 2010
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2009.03636.x
Subject(s) - hydrocortisone , congenital adrenal hyperplasia , medicine , endocrinology , pharmacodynamics , glucocorticoid , corticosteroid , androstenedione , pharmacokinetics , hormone , area under the curve , adrenocorticotropic hormone , androgen
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.