Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study
2016 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 175, no 1, 85-93 p.Article in journal (Refereed) PublishedText
Objective: Oral 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 5-20 mg and assess intrasubject variability. Methods: Thirty-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 x 5), and 20 mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24 h 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. Results: DR-HC 20 mg provided higher than endogenous cortisol plasma concentrations 0-4 h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (C-max) was 82.0 and 178.1 ng/mL, while mean area under the concentration-time curve (AUC)(0-infinity) was 562.8 and 1180.8 h x ng/mL with DR-HC 5 and 20 mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20 mg. All exposure PK parameters were less than dose proportional (slope < 1). PK differences between ethnicities were explained by body weight differences. Conclusions: DR-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.
Place, publisher, year, edition, pages
2016. Vol. 175, no 1, 85-93 p.
Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:uu:diva-299837DOI: 10.1530/EJE-15-1212ISI: 000378754700014PubMedID: 27129362OAI: oai:DiVA.org:uu-299837DiVA: diva2:950288