Melin, J., Hartung, N., Parra-Guillen, Z.P. et al. (3 more authors) (2019) The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing. Clinical Endocrinology, 91 (1). pp. 33-40. ISSN 0300-0664
Abstract
CONTEXT: Optimisation of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex 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 after hydrocortisone administration. DESIGN AND 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 on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. 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 11.9%; the amplitude for the 24 h and 12 h cosine functions were relatively small (24 h: 5.53%, 12 h: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure 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 (≤12.2%), also regarding the free cortisol concentration and free fraction (≤11.7%). CONCLUSIONS: CBG has a circadian rhythm but the difference in cortisol exposure is ≤12.2% between times of highest and lowest CBG concentrations; therefore hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.
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Copyright, Publisher and Additional Information: | © 2019 Wiley. This is an author produced version of a paper subsequently published in Clinical Endocrinology. Uploaded in accordance with the publisher's self-archiving policy. | ||||
Keywords: | Circadian Rhythm; Hydrocortisone; Pharmacokinetics; Transcortin | ||||
Dates: |
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals | ||||
Funding Information: |
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 20 Mar 2019 11:12 | ||||
Last Modified: | 19 Nov 2021 15:09 | ||||
Status: | Published | ||||
Publisher: | Wiley | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1111/cen.13969 | ||||
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