title: Modified-release hydrocortisone to provide circadian cortisol profiles.
abstract: BACKGROUND
  Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm.
  
  
  OBJECTIVE
  Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles.
  
  
  METHODS
  The study was performed at a Clinical Research Facility.
  
  
  METHODS
  Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen.
  
  
  RESULTS
  The key variables in the physiological cortisol profile included: peak 15.5 microg/dl (95% reference range 11.7-20.6), acrophase 0832 h (95% confidence interval 0759-0905), nadir less than 2 microg/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) microg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels.
  
  
  CONCLUSIONS
  By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.
authors.affiliation: Academic Unit of Diabetes, School of Medicine, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, United Kingdom.
authors.forename: Miguel
authors.initials: M
authors.lastname: Debono
authors.forename: Cyrus
authors.initials: C
authors.lastname: Ghobadi
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: Hiep
authors.initials: H
authors.lastname: Huatan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: John
authors.initials: J
authors.lastname: Newell-Price
authors.forename: Ken
authors.initials: K
authors.lastname: Darzy
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D002940:Circadian Rhythm / Q000502:physiology*; D003430:Cross-Sectional Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone