Four-compartment diffusion model of cortisol disposition: Comparison to three alternative models in current clinical use

Abstract

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 four models were independently applied to cortisol concentration data obtained for the hydrocortisone bolus experiment (20 mg) in two clinical groups: healthy volunteers (HV, n = 6) and 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 RM-ANOVA. Models and respective parameter solutions were compared by mathematical and simulation analyses, and an assessment tool was used to compare performance characteristics. Results Cortisol half-lives differed significantly between models (all P < 0.001) with significant model-group interaction (P = 0.02). In comparative analysis, Model 4 solutions yielded significantly reduced free cortisol half-life, improved fit to experimental data (both P < 0.01), and superior model performance. Conclusions 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.