Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study.
BACKGROUND
Endogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile.


OBJECTIVE
To determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose.


METHODS
A randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm.


METHODS
The single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC-MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis.


RESULTS
The time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18-24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC-MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional.


CONCLUSIONS
The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.
Johannsson
Gudmundur
G
Department of Endocrinology, Sahlgrenska Academy, Sahlgrenska University Hospital, Grona Straket 8 Clinical Pharmacology, Sahlgrenska Academy, Gothenburg University, SE-413 45 Gothenburg, Sweden. gudmundur.johannsson@gu.se
Bergthorsdottir
Ragnhildur
R
Nilsson
Anna G
AG
Lennernas
Hans
H
Hedner
Thomas
T
Skrtic
Stanko
S
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D004435:Eating; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013607:Tablets; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D013607:Tablets; D006854:Hydrocortisone