Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

Abstract

ObjectiveOral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure−time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5–20mg and assess intrasubject variability.MethodsThirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20−55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography−tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration−time profiles.ResultsDR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0−4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration−time curve (AUC)0−∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences.ConclusionsDR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional – an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

Dual-release hydrocortisone vs conventional glucocorticoids in adrenal insufficiency

“…The recent formulation of DR-HC has been shown to ensure an effective concentration of plasma cortisol, simulating the profile of physiological cortisol (31, 32). Several studies have shown that DR-HC treatment is associated with a reduction in weight, WC, systolic and diastolic blood pressure, HbA1c and lipids and an improvement of quality of life (6, 7, 9, 15).…”

Improved insulin sensitivity and secretion in prediabetic patients with adrenal insufficiency on dual‐release hydrocortisone treatment: a 36‐month retrospective analysis

“…The recent formulation of DR‐HC has been demonstrated to provide an effective plasma cortisol concentration with a peak of 400‐600 nmol/L in the morning, a level of 200 nmol/L in the afternoon and a cortisol‐free interval during the night, mimicking the physiological cortisol profile …”

“…Recently, a novel once‐daily dual‐release HC (DR‐HC) was approved for treatment of AI in adults, characterized by an immediate‐release fraction of HC in the outer layer of the tablet and an extended‐release fraction in the core, able to provide an adequate concentration of cortisol within 50 minutes after administration, half cortisol plasmatic concentration for 6 hours thereafter and a minimal cortisol level 18‐24 hours after intake . This formulation tends to provide a cortisol exposure‐time profile close to the physiological one, improving anthropometric parameters, HbA1c and questionnaire‐related quality of life and appears to be safe even in the long‐term …”

Pediatric Adrenal Insufficiency: Diagnosis, Management, and New Therapies

“…A dual-release hydrocortisone preparation is given once daily in the morning, with immediate release coating that is rapidly absorbed, followed by a slow release from the core of tablet. Studies of this hydrocortisone formulation in adults with Addison's disease have shown to achieve physiologic cortisol profile, reduce central adiposity, and improve metabolic parameters, as well as quality of life [ 50 , 51 ]. Once-daily, modified–release hydrocortisone treatment in patients with AI restores a more physiologic circadian cortisol rhythm, normalizes the immune cell profile, and reduces recurrent infections, compared to treatment with conventional glucocorticoid replacement therapy [ 52 ].…”