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. 2023 Jan;13(1):1-8.
doi: 10.1007/s13346-022-01183-w. Epub 2022 May 26.

Chronotherapy based on modified-release hydrocortisone to restore the physiological cortisol diurnal rhythm

Martin J Whitaker  1   2 , Hiep Huatan  1 , Richard J Ross  3   4
Affiliations

Chronotherapy based on modified-release hydrocortisone to restore the physiological cortisol diurnal rhythm

Martin J Whitaker et al. Drug Deliv Transl Res. 2023 Jan.

Abstract

In this inspirational note, we describe the development of an endocrine chronotherapy to restore the physiological rhythm of the essential adrenal stress hormone, cortisol. The challenges included demonstrating the circadian rhythm of the drug target, creating a drug formulation that replicated that rhythm and then proving benefit in clinical trials. The physiological cortisol circadian rhythm is well defined with cortisol levels high on waking and low on going to sleep. We experimented with different formulation technologies including modified-release tablets and multi-particulates to replicate the cortisol rhythm where absent through disease. We describe the development of Efmody®, a modified-release formulation of hydrocortisone, which replicates the cortisol diurnal rhythm and improves the disease control of congenital adrenal hyperplasia, the commonest hereditary form of adrenal insufficiency. This program shows it is possible, through modified-release technology, to treat chronic endocrine diseases with physiological replacement to preserve health for life.

Keywords: Chronotherapy; Circadian; Cortisol; Efmody; Hormone; Hydrocortisone; Multi-particulate.

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Conflict of interest statement

RJR is a director; MJW is an employee; and HH is a consultant to Diurnal Ltd.

Figures

Fig. 1
Fig. 1
The circadian rhythm of cortisol (yellow) and thrice-daily immediate-release hydrocortisone (HC) replacement (yellow) showing variable pharmacokinetic cortisol replacement during the day time period (ca. 07:00 h to 22:00 h) but with no overnight replacement of cortisol during the nighttime period (ca. 22:00 h to 07:00 h). Adapted from Debono et al. JCEM [6]
Fig. 2
Fig. 2
The hypothalamic–pituitary–adrenal (HPA) axis: blue arrows indicate positive cortisol production drive, and the red arrows indicate negative feedback
Fig. 3
Fig. 3
Evolution of Efmody® from concept to performance in patients: a micro-particulate formulation; b in vitro dissolution of DIURF-000 (in blue) compared to target product profile (orange); c phase II cortisol profile in patients with CAH treated with Efmody® (blue) compared to normal cortisol rhythm (orange)
Fig. 4
Fig. 4
Efmody® provides androgen control in adults with a reduction in steroid dose: a pivotal phase III study confirms control of the key androgen 17-OHP throughout the 24-h period and especially in the critical morning period with Efmody® after 24 weeks (grey shading indicates the reference range of 17OHP derived from healthy individuals); b in the long-term extension study, optimal disease control was maintained at a reduced daily dose c that is recommended for adrenal replacement
See this image and copyright information in PMC

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