A modified-release formulation of hydrocortisone that aims to mimic the normal pattern of cortisol secretion could provide a novel option for the medical management of patients with congenital adrenal hyperplasia (CAH), say the authors of a report published in Clinical Endocrinology.
Glucocorticoid therapy for CAH can be a challenge: a fine balance must be maintained between adequate control of the androgen excess that results from 21-hydroxylase deficiency and the adverse effects associated with overtreatment. In healthy individuals, production of cortisol displays a distinct circadian rhythm: levels reach a nadir at around midnight and peak early in the morning. Glucocorticoid formulations that replicate this profile might, therefore, overcome the shortcomings of traditional glucocorticoid therapy.
In response to this need, a novel oral formulation of hydrocortisone has been developed that allows delayed and sustained release of the drug. Chronocort® (Phoqus Pharmaceuticals, West Malling, UK) has already undergone phase I testing in healthy volunteers. The results of these studies demonstrated that administration of Chronocort® after dexamethasone-induced suppression of endogenous cortisol production results in a physiological profile of cortisol secretion. Verma and colleagues have now evaluated Chronocort® in patients with CAH.
The researchers enrolled 14 patients (mean age 26.8 years) in this phase II, open-label, crossover study of Chronocort® versus a conventional, immediate-release, oral hydrocortisone preparation. After screening, participants switched from their usual glucocorticoid regimen to thrice-daily conventional hydrocortisone (10 mg at 0800 h, 5 mg at 1500 h and 15 mg at 2200 h) for 1 week, followed by once-daily Chronocort® (30 mg at 2200 h) for 4 weeks. Steady state, 24 h sampling of the serum levels of cortisol, 17-hydroxyprogesterone, androstenedione and adrenocorticotropic hormone was performed to assess the pharmacokinetic and pharmacodynamic profiles of Chronocort®.
As expected, conventional hydrocortisone therapy resulted in three peaks of cortisol; by contrast, Verma et al. found only a single peak (at ∼0600 h) after administration of Chronocort®. Morning levels of 17-hydroxyprogesterone were lower after treatment with Chronocort® than after conventional hydrocortisone therapy, which indicated improved control of adrenal androgen production. However, afternoon levels of 17-hydroxyprogesterone, androstenedione and adrenocorticotropic hormone were elevated during treatment with Chronocort®. The researchers conclude that a single dose of Chronocort® might not be sufficient to provide full cortisol coverage.
The next step will be to perform additional studies of increased duration that allow twice-daily administration of Chronocort® and dose adjustments as and when required. In the meantime, Verma and colleagues' preliminary work provides proof of the principle that a physiological profile of cortisol can be achieved and lays the foundation for a new strategy in the treatment of patients with CAH.
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Heath, V. Novel formulation of hydrocortisone shows promise. Nat Rev Endocrinol 5, 468 (2009). https://doi.org/10.1038/nrendo.2009.133
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DOI: https://doi.org/10.1038/nrendo.2009.133
