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

Gudmundur Johannsson,Stanko Skrtic,Hans Lennernäs,Claudio Marelli,Kevin Rockich

doi:10.1530/eje-15-1212

Gudmundur Johannsson, Stanko Skrtic + Show 3 more

Open Access

https://doi.org/10.1530/eje-15-1212

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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.

Highlights

Adrenal insufficiency (AI) is a life-threatening orphan disease that requires daily glucocorticoid replacement to increase cortisol concentrations to pre-disease values [1, 2]
The PK analysis plan (PKAP)-defined evaluable PK profile had to have a good estimate of the terminal elimination phase, that is, an adjusted R2 goodness-of-fit statistic >80%, and sufficient data to estimate the area under the concentration−time curve (AUC) with ≤10% of the integrand extrapolated
The Japanese and Caucasian groups were well matched for age, BMI, and sex, but the Japanese group had a lower mean (s.d.) weight of 66.5 (9.7) kg compared with the Caucasian group of 72.2 (9.6) kg due to two outliers in the Japanese group with very low weights (48.8 and 52.4 kg)

Summary

Introduction

Adrenal insufficiency (AI) is a life-threatening orphan disease that requires daily glucocorticoid replacement to increase cortisol concentrations to pre-disease values [1, 2]. Hydrocortisone is the most commonly used glucocorticoid replacement therapy and requires multiple daily oral administrations to provide an adequate cortisol concentration−time profile [1]. In a typical dosing regimen, hydrocortisone is taken two or three times per day, with the highest dose in the morning, a lower dose at midday and, if necessary, a third dose in the late afternoon or early evening [3]. Patients with chronic AI often experience adrenal crisis despite treatment and education, with an associated mortality rate of 6.3% [9]

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