title: A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia.
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Reproductive Biology and Medicine Branch, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
authors.forename: Somya
authors.initials: S
authors.lastname: Verma
authors.forename: Carol
authors.initials: C
authors.lastname: Vanryzin
authors.forename: Ninet
authors.initials: N
authors.lastname: Sinaii
authors.forename: Mimi S
authors.initials: MS
authors.lastname: Kim
authors.forename: Lynnette K
authors.initials: LK
authors.lastname: Nieman
authors.forename: Shayna
authors.initials: S
authors.lastname: Ravindran
authors.forename: Karim A
authors.initials: KA
authors.lastname: Calis
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy*; D000328:Adult; D019540:Area Under Curve; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged
chemical_list: D003692:Delayed-Action Preparations; D006854:Hydrocortisone