title: An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure.
abstract: OBJECTIVE
  It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology.
  
  
  METHODS
  Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population.
  
  
  METHODS
  Field laboratories and clinical research facility.
  
  
  RESULTS
  Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily 'toothbrush' regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg.
  
  
  CONCLUSIONS
  A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure.
authors: Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK (M.D., R.J.R); Diurnal Ltd, Cardiff, UK (M.W., H.H.); National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (D.M.); Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK (W.A.).
authors: Martin
authors: M
authors: Whitaker
authors: Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK (M.D., R.J.R); Diurnal Ltd, Cardiff, UK (M.W., H.H.); National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (D.M.); Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK (W.A.).
authors: Miguel
authors: M
authors: Debono
authors: Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK (M.D., R.J.R); Diurnal Ltd, Cardiff, UK (M.W., H.H.); National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (D.M.); Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK (W.A.).
authors: Hiep
authors: H
authors: Huatan
authors: Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK (M.D., R.J.R); Diurnal Ltd, Cardiff, UK (M.W., H.H.); National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (D.M.); Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK (W.A.).
authors: Deborah
authors: D
authors: Merke
authors: Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK (M.D., R.J.R); Diurnal Ltd, Cardiff, UK (M.W., H.H.); National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (D.M.); Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK (W.A.).
authors: Wiebke
authors: W
authors: Arlt
authors: Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK (M.D., R.J.R); Diurnal Ltd, Cardiff, UK (M.W., H.H.); National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (D.M.); Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK (W.A.).
authors: Richard J
authors: RJ
authors: Ross
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000188:drug therapy*; D000328:Adult; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002940:Circadian Rhythm / Q000502:physiology; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000008:administration & dosage; D004285:Dogs; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D012995:Solubility
chemical_list: D003692:Delayed-Action Preparations; D003907:Dexamethasone; D006854:Hydrocortisone
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