Four-Compartment Diffusion Model of Cortisol Disposition: Comparison With 3 Alternative Models in Current Clinical Use

Richard I Dorin; Frank K Urban 3rd; Ilias Perogamvros; Clifford R Qualls

doi:10.1210/jendso/bvac173

Four-Compartment Diffusion Model of Cortisol Disposition: Comparison With 3 Alternative Models in Current Clinical Use

J Endocr Soc. 2022 Nov 14;7(2):bvac173. doi: 10.1210/jendso/bvac173. eCollection 2022 Dec 15.

Authors

Richard I Dorin^{1

2}, Frank K Urban 3rd³, Ilias Perogamvros⁴, Clifford R Qualls^{5

6}

Affiliations

¹ Department of Medicine, New Mexico Veterans Affairs Healthcare System, Albuquerque, NM 87108, USA.
² Department of Medicine and Biochemistry & Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
³ Department of Electrical and Computer Engineering, Florida International University, Miami, FL 33199, USA.
⁴ Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, University of Manchester, Manchester M13 9PL, UK.
⁵ Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM 87131, USA.
⁶ Department of Research, New Mexico Veterans Affairs Healthcare System, Albuquerque, NM 87108, USA.

Abstract

Context: Estimated rates of cortisol elimination and appearance vary according to the model used to obtain them. Generalizability of current models of cortisol disposition in healthy humans is limited.

Objective: Development and validation of a realistic, mechanistic model of cortisol disposition that accounts for the major factors influencing plasma cortisol concentrations in vivo (Model 4), and comparison to previously described models of cortisol disposition in current clinical use (Models 1-3).

Methods: The 4 models were independently applied to cortisol concentration data obtained for the hydrocortisone bolus experiment (20 mg) in 2 clinical groups: healthy volunteers (HVs, n = 6) and corticosteroid binding globulin (CBG)-deficient (n = 2). Model 4 used Fick's first law of diffusion to model free cortisol flux between vascular and extravascular compartments. Pharmacokinetic parameter solutions for Models 1-4 were optimized by numerical methods, and model-specific parameter solutions were compared by repeated measures analysis of variance. Models and respective parameter solutions were compared by mathematical and simulation analyses, and an assessment tool was used to compare performance characteristics of the four models evaluated herein.

Results: Cortisol half-lives differed significantly between models (all P < .001) with significant model-group interaction (P = .02). In comparative analysis, Model 4 solutions yielded significantly reduced free cortisol half-life, improved fit to experimental data (both P < .01), and superior model performance.

Conclusion: The proposed 4-compartment diffusion model (Model 4) is consistent with relevant experimental observations and met the greatest number of empiric validation criteria. Cortisol half-life solutions obtained using Model 4 were generalizable between HV and CBG-deficient groups and bolus and continuous modes of hydrocortisone infusion.

Keywords: albumin; compartmental modeling; computer-assisted; corticosteroid binding globulin (CBG); cortisol; hydrocortisone; metabolic clearance rate; numerical analysis; septic shock.

Published by Oxford University Press on behalf of the Endocrine Society 2022.