title: Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study.
abstract: 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 5-20mg 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 (3×5), 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.
  
  
  RESULTS
  DR-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.
  
  
  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.
authors.affiliation: Department of EndocrinologyInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden gudmundur.johannsson@medic.gu.se.
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Johannsson
authors.affiliation: Department of PharmacyUppsala University, Uppsala, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
authors.affiliation: Shire International GmbHZug, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Marelli
authors.affiliation: Shire PLCWayne, Pennsylvania, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rockich
authors.affiliation: Department of EndocrinologyInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden AstraZeneca R&DMölndal, Sweden.
authors.forename: Stanko
authors.initials: S
authors.lastname: Skrtic
mesh_terms: D000309:Adrenal Insufficiency / Q000188:drug therapy*; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D006854:Hydrocortisone