title: Replacement therapy of oral hydrocortisone in adrenal insufficiency: the influence of gastrointestinal factors.
abstract: BACKGROUND
  Replacing glucocorticoids in primary adrenal insufficiency (AI) or Addison's disease (AD) is today based on oral replacement therapy with hydrocortisone in a conventional immediate-release tablet. It is recognised that physiological gastrointestinal factors may have a strong influence on the plasma concentration-time profile of hydrocortisone. Hydrocortisone has a sufficiently high permeability in both the small and large intestine, but in vivo dissolution from the available oral product is limited at higher doses. The short elimination half-life of hydrocortisone (approximately 1.5 h) when given in traditional immediate-release dosage forms requires two or more dose administrations per day, with high peaks and low trough values in between. The endogenous secretion of cortisol from the adrenal cortex follows a distinct diurnal pattern, with increasing and high plasma levels of cortisol early in the morning (approximately 05.00-08.00 h), intermediate levels in the afternoon, low levels in the evening and a cortisol-free interval at night. There is, therefore, a clinical need for an improved drug delivery product that more closely follows the circadian pattern of cortisol in plasma.
  
  
  OBJECTIVE
  The pharmaceutical and biopharmaceutical properties of the dosage form containing hydrocortisone will determine intestinal absorption rate and the plasma concentration-time profile of hydrocortisone (cortisol). Factors that cause or result in pharmacokinetic variability should be understood and avoided where possible.
  
  
  METHODS
  A literature search was performed with the aim of covering the field of gastrointestinal drug absorption of hydrocortisone in AD.
  
  
  CONCLUSIONS
  Novel oral drug delivery principles for facilitation of once-daily dosing and providing a safe and physiologically based plasma concentration-time profile of hydrocortisone in replacement therapy are discussed. Development of new drug formulations is ongoing and will certainly lead to an improved replacement therapy of AD with hydrocortisone. Of special interest is a therapy based on once-daily treatment and less fluctuating plasma concentrations of hydrocortisone (cortisol).
authors.affiliation: Uppsala University, Pharmacy Department, Box 580, Husargatan 3, SE-751 23, Uppsala, Sweden. hans.lennernas@telia.com
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
authors.forename: Stanko
authors.initials: S
authors.lastname: Skrtic
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Johannsson
mesh_terms: D000284:Administration, Oral; D000309:Adrenal Insufficiency / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002626:Chemistry, Pharmaceutical; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D005769:Gastrointestinal Motility; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000172:deficiency / Q000493:pharmacokinetics; D020249:Hormone Replacement Therapy; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000172:deficiency / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D010539:Permeability; D013607:Tablets
chemical_list: D005938:Glucocorticoids; D013607:Tablets; D006854:Hydrocortisone