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 23:0002:00, whereas the highest was observed at 15:0018:00. 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.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology