Whitaker, M.J., Debono, M., Huatan, H. et al. (3 more authors) (2014) An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure. Clinical Endocrinology, 80 (4). pp. 554-561. ISSN 0300-0664
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.
Design and Measurements Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population.
Setting 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.
Conclusion 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014 Wiley. This is an author produced version of a paper subsequently published in Clinical Endocrinology. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 13 Feb 2017 12:26 |
Last Modified: | 21 Mar 2018 14:43 |
Published Version: | https://doi.org/10.1111/cen.12316 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1111/cen.12316 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:110830 |