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

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

doi:10.1111/cen.12316

Cited by 93 publications

(60 citation statements)

References 24 publications

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“…Plenadren® (ViroPharma SPRL, Brussels, Belgium) is currently available on the market for the treatment of AI, which provides a rapid increase in cortisol levels after intake in the morning followed by a gradual decrease over the day to almost undetectable levels in the night similar to the normal circadian rhythm [57]. Maybe even more promising for the treatment of AI in 21OHD is Chronocort®, which is currently being tested in clinical trials [52,58,59]. In 2 doses it might be able to provide an optimal cortisol profile to mimic the physiology of GC production and suppress adrenal androgens.…”

Section: Treatment Of Paimentioning

confidence: 99%

Novel Insight into Etiology, Diagnosis and Management of Primary Adrenal Insufficiency

Malíková¹,

Flück

2014

Horm Res Paediatr

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Primary adrenal insufficiency (PAI) is a rare condition in childhood which is either inherited (mostly) or acquired. It is characterized by glucocorticoid and maybe mineralocorticoid deficiency. The most common form in children is 21-hydroxylase deficiency, which belongs to the steroid biosynthetic defects causing PAI. Newer forms of complex defects of steroid biosynthesis are P450 oxidoreductase deficiency and (apparent) cortisone reductase deficiency. Other forms of PAI include metabolic disorders, autoimmune disorders and adrenal dysgenesis, e.g. the IMAGe syndrome, for which the underlying genetic defect has been recently identified. Newer work has also expanded the genetic causes underlying isolated, familial glucocorticoid deficiency (FGD). Mild mutations of CYP11A1 or StAR have been identified in patients with FGD. MCM4 mutations were found in a variant of FGD in an Irish travelling community manifesting with PAI, short stature, microcephaly and recurrent infections. Finally, mutations in genes involved in the detoxification of reactive oxygen species were identified in patients with unsolved FGD. Most mutations were found in the enzyme nicotinamide nucleotide transhydrogenase, which uses the mitochondrial proton pump gradient to produce NADPH. NADPH is essential in maintaining high levels of reduced forms of antioxidant enzymes for the reduction of hydrogen peroxide. Similarly, mutations in the gene for TXNRD2 involved in this system were found in FGD patients, suggesting that the adrenal cortex is particularly susceptible to oxidative stress.

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Section: Treatment Of Paimentioning

confidence: 99%

Novel Insight into Etiology, Diagnosis and Management of Primary Adrenal Insufficiency

Malíková¹,

Flück

2014

Horm Res Paediatr

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“…Chronocort was designed to release hydrocortisone in the last third of the small bowel to allow for delayed and sustained absorption (6). The multi-particulate formulation approach was selected to provide more predictable, reproducible gastrointestinal transit over single-unit oral dosage forms (14).…”

Section: Discussionmentioning

confidence: 99%

Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia

Karunasena

Margetson

Neal

et al. 2017

European Journal of Endocrinology

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BackgroundWe developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm.Subjects and methodsIn vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone.ResultsIn vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer Tmax (fed vs fasted: 6.75 h vs 4.5 h, P = 0005) and lower Cmax (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71–85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0t for fed/fasted was 108.33% (102.30–114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58–126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0–125.0%: Geo LSmean ratio (CI) for AUC0t 112.73% (105.33–120.65%).ConclusionsGastric pH ≤6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone.

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“…108 The cortisol time-exposure profile achieved using the once-daily dualrelease hydrocortisone treatment has been accompanied by an improvement in several clinical outcomes in patients with primary and secondary adrenal insufficiency. [108][109][110][111][112][113] Prospective trials have shown improved cardiovascular risk factors, glucose metabolism and quality of life in comparison with conventional treatment. 114 Interestingly, the daily doses of immediate release hydrocortisone and dual-release hydrocortisone was similar, suggesting that the pattern of hydrocortisone delivery and the circadian cortisol exposure-time profile may therefore be as crucial as the total daily dose in terms of patient outcomes.…”

Section: Timing/pat Tern Of Delivery Of G Luco Corti Coidsmentioning

confidence: 99%

Factors impacting on the action of glucocorticoids in patients receiving glucocorticoid therapy

Dineen

Stewart

Sherlock

2018

Clinical Endocrinology

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Glucocorticoids (GCs) are steroid hormones, which are essential for life. They are secreted by the adrenal cortex under the control of the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids are essential for the normal function of most organ systems and, in both, excess and deficiency can lead to significant adverse consequences. Adrenal insufficiency (AI) is a rare, life-threatening disorder characterized by insufficient production of corticosteroid hormones. Primary AI is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids despite normal or increased adrenocorticotropin hormone (ACTH). Secondary AI is adrenal hypofunction due to insufficient amount of ACTH produced by the pituitary gland. Conventional treatment of both primary and secondary adrenal insufficiencies involves lifelong glucocorticoid replacement therapy. The role of cortisol deficiency and the impact of hydrocortisone replacement on morbidity and mortality in this patient group are under increasing scrutiny. Established glucocorticoid replacement regimens do not completely mirror endogenous hormonal production, and their monitoring to ensure optimum therapy is hampered by the lack of reliable biomarkers of hormone sufficiency. A further confounding issue is the tissue-specific regulation of glucocorticoid through the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) with research focusing on the role of this prereceptor regulation in the development of adverse metabolic features in patients. This review defines the factors influencing glucocorticoid action in patients with adrenal insufficiency receiving glucocorticoid therapy.

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

Cited by 93 publications

References 24 publications

Novel Insight into Etiology, Diagnosis and Management of Primary Adrenal Insufficiency

Novel Insight into Etiology, Diagnosis and Management of Primary Adrenal Insufficiency

Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia

Factors impacting on the action of glucocorticoids in patients receiving glucocorticoid therapy

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