An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure

Martin J Whitaker; Miguel Debono; Hiep Huatan; Deborah P Merke; Wiebke Arlt; Richard J Ross

doi:10.1111/cen.12316

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure

Martin J Whitaker, Miguel Debono, Hiep Huatan, Deborah P Merke, Wiebke Arlt, Richard J Ross

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-review

59 Citations (Scopus)

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.

Original language	English
Pages (from-to)	554-61
Number of pages	8
Journal	Clinical Endocrinology
Volume	80
Issue number	4
DOIs	https://doi.org/10.1111/cen.12316
Publication status	Published - Apr 2014

Keywords

Adolescent
Adrenal Insufficiency
Adult
Animals
Biological Availability
Chemistry, Pharmaceutical
Circadian Rhythm
Delayed-Action Preparations
Dexamethasone
Dogs
Humans
Hydrocortisone
Male
Middle Aged
Solubility

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10.1111/cen.12316

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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.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.",

keywords = "Adolescent, Adrenal Insufficiency, Adult, Animals, Biological Availability, Chemistry, Pharmaceutical, Circadian Rhythm, Delayed-Action Preparations, Dexamethasone, Dogs, Humans, Hydrocortisone, Male, Middle Aged, Solubility",

author = "Whitaker, {Martin J} and Miguel Debono and Hiep Huatan and Merke, {Deborah P} and Wiebke Arlt and Ross, {Richard J}",

note = "{\textcopyright} 2013 John Wiley & Sons Ltd.",

year = "2014",

month = apr,

doi = "10.1111/cen.12316",

language = "English",

volume = "80",

pages = "554--61",

journal = "Clinical Endocrinology",

issn = "0300-0664",

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TY - JOUR

T1 - An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure

AU - Whitaker, Martin J

AU - Debono, Miguel

AU - Huatan, Hiep

AU - Merke, Deborah P

AU - Arlt, Wiebke

AU - Ross, Richard J

PY - 2014/4

Y1 - 2014/4

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adrenal Insufficiency

KW - Adult

KW - Animals

KW - Biological Availability

KW - Chemistry, Pharmaceutical

KW - Circadian Rhythm

KW - Delayed-Action Preparations

KW - Dexamethasone

KW - Dogs

KW - Humans

KW - Hydrocortisone

KW - Male

KW - Middle Aged

KW - Solubility

U2 - 10.1111/cen.12316

DO - 10.1111/cen.12316

M3 - Article

C2 - 23980724

SN - 0300-0664

VL - 80

SP - 554

EP - 561

JO - Clinical Endocrinology

JF - Clinical Endocrinology

IS - 4

ER -

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure

Abstract

Keywords

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