ESPE Abstracts (2018) 89 P-P1-010

The Circadian Rhythm of Cortisol Binding Globulin has Little Impact on Cortisol Exposure after Hydrocortisone Dosing

Johanna Melina, Niklas Hartunga, Zinnia Parra-Guillena, Martin Whitakerb, Richard Rossc & Charlotte Klofta

aFreie Universitaet, Berlin, Germany; bDiurnal Ltd, Cardiff, UK; cUniveristy of Sheffield, Sheffield, UK

Background: Optimisation of hydrocortisone replacement therapy remains challenging due to complex pharmacokinetics as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm.

Objective: A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure during hydrocortisone replacement therapy.

Methods: CBG was measured over 24 h in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact of hydrocortisone administration at different clock times and the changing CBG concentrations on cortisol exposure.

Results: The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 μg/ml and inter-individual variability CV 11.9%; the amplitude for the 24 and 12 h cosine functions were relatively small (24 h: 5.53%, 12 h: 2.87%) and CmaxCBG at 18:00 h and CminCBG 02:00 h. In simulations, the lowest cortisol exposure (AUC, Cmax) was observed after administration of hydrocortisone at 23:00–02:00, whereas the highest was observed at 15:00–18:00. The differences between the highest and lowest exposure were minor (<11%).

Conclusions: CBG has a circadian rhythm but the difference in cortisol exposure is <11% between times of highest and lowest CBG concentrations; therefore hydrocortisone dose adjustment based on time of dosing is not required.

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