Endocrine Abstracts

Novel biopharmaceutical techniques have allowed the development of a hydrocortisone modified release (MR) tablet (once-daily administration for replacement therapy in adrenal insufficiency) mimicking more closely the physiological serum cortisol profile. Robust bioavailability is needed to secure this new treatment safety.

Aims: To compare single-dose pharmacokinetics (PK) of MR tablets manufactured at two different sites by assessing intra-subject variability (dose range: 5–20 mg).

Methods: Thirty-two healthy men and women (20–55 years; BMI: 18–30 kg/m²) were enrolled into a randomized, open-label, four-period crossover, single-dose PK study with collection of baseline 24 h endogenous cortisol secretion. During four periods 5, 15, 20 (new manufacturing site R), and 20 mg (reference site G) were administered orally at 0800 h after overnight fast. Endogenous cortisol secretion during PK sampling was suppressed using dexamethasone. PK parameters were determined using non-compartmental analysis. Plasma cortisol was measured using LC–MS/MS.

Results: Within-individual comparison between the endogenous profile and the 20 mg tablet showed hydrocortisone treatment provided higher than endogenous concentrations 0–4 h post-dose and similar concentrations 5–15 h post-dose. Mean hydrocortisone Cmax (S.D.) was 82.0 (18.2), 148.8 (29.3), 177.1 (25.5), and 178.0 (28.1) ng/ml and mean AUC∞ was 523.8 (128.0), 1024.5 (158.1), 1178.2 (222.2), and 1191.4 (190.9) h×ng/ml for 5, 15, 20 mg R treatments, and 20 mg G treatment respectively. Bioequivalence, defined as the 90% CI being within the 80 125% limits, was demonstrated. Within-subject variability was below 15% for all examined PK parameters for the 20 mg R and G MR tablet oral administration. Exposure PK parameters were found to be less than dose proportional, i.e. AUC∞ with a 0.78 slope (95% CI: 0.70–0.85) in the 5–20 mg dose range.

Conclusions: Once daily MR hydrocortisone demonstrates a physiological cortisol exposure during the day. Within-individual day-to-day PK variability is very low underpinning product safety for replacement therapy. Hydrocortisone PK is less than dose proportional, an important PK property of oral hydrocortisone that should be considered in the intercurrent illness management of adrenal insufficiency.

Disclosure: This work was supported by Shire.