Endocrine Abstracts (2013) 32 P1 | DOI: 10.1530/endoabs.32.P1

Chronocort[reg], a multiparticulate modified release hydrocortisone formulation, shows dose linearity and twice daily dosing provides physiological cortisol exposure

Richard Ross1,2, Martin Whitaker1,2, Miguel Debono1, Hiep Huatan2, Wiebke Arlt3 & Deborah Merke4

1University of Sheffield, Sheffield, UK; 2Diurnal Ltd, Cardiff, UK; 3University of Birmingham, Birmingham, UK; 4The National Institutes of Health, Bethesda, Maryland, USA.

Cortisol has a distinct circadian rhythm; levels rise from 0300 h to peak within an hour of waking and gradually decline until 1800 h before a quiescent period lasting from 1800 to 0300 h. Current hydrocortisone replacement regimens are unable to replicate this rhythm and we have been investigating modified release technology. Our initial formulation, using tableting technology, demonstrated it was possible to replicate the overnight rise in cortisol but the tablet had reduced bioavailability (Debono et al. Journal of Clinical Endocrinology and Metabolism 2009 94 1548–1554). We have now investigated the use of multiparticulate technology which has flexibility for variable doses using the same formulation. We tested six multiparticulate formulations and identified a formulation, DIURF-006, that provided the optimal overnight cortisol profile. We have now tested dose-proportionality and twice daily dosing for DIURF-006 using 5, 10, and 20 mg administered as a single-dose at night and 30 mg administered as a 20 mg dose at night and a 10 mg dose the following morning in 16 healthy male volunteers in whom endogenous cortisol levels were suppressed with dexamethasone. Dosing was randomised, all studies were separated by 1 week wash-out period and cortisol levels measured by LC–MS/MS. Serum cortisol levels were shown to increase linearly with dose, although dose proportionality was not at unity as shown in the slope of the regression line: Cmax for 5, 10, 20, and 30 mg was 288, 440, 641, and 665 nmol/l (slope: 0.49, 95% CI 0.42–0.56) and AUC0-t was 1586, 2530, 3919, and 5610 h×nmol/l (slope: 0.69, 95% CI 0.65–0.73). The AUC and Cmax for twice daily dosing were similar to that reported for normal diurnal cortisol secretion. In conclusion, Chronocort® formulation DIURF-006, provides a linear increase in Cmax and cortisol AUC over a dose range from 5 to 30 mg and the Cmax and AUC are similar to that previously reported for physiological cortisol levels.

Acknowledgements: This research was supported in part by the Intramural Research Program of the NIH.

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