Modified-release hydrocortisone to provide circadian cortisol profiles.
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.
Debono
Miguel
M
Academic Unit of Diabetes, School of Medicine, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, United Kingdom.
Ghobadi
Cyrus
C
Rostami-Hodjegan
Amin
A
Huatan
Hiep
H
Campbell
Michael J
MJ
Newell-Price
John
J
Darzy
Ken
K
Merke
Deborah P
DP
Arlt
Wiebke
W
Ross
Richard J
RJ
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
D003692:Delayed-Action Preparations; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone