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

Area of Science:

• Pharmacology
• Physiology
• Mathematical Modeling

Background:

• Cortisol elimination and appearance rates vary based on the model used, limiting generalizability in healthy humans.
• Current models of cortisol disposition have limitations in accurately reflecting in vivo dynamics.

Purpose of the Study:

• To develop and validate a mechanistic model (Model 4) for cortisol disposition, incorporating key factors influencing plasma cortisol concentrations.
• To compare the performance of Model 4 against three existing models (Models 1-3).

Main Methods:

• Four models were applied to cortisol concentration data from healthy volunteers and corticosteroid binding globulin-deficient individuals.
• Model 4 utilized Fick's first law of diffusion to simulate free cortisol flux between vascular and extravascular compartments.
• Pharmacokinetic parameters were optimized numerically, and model performance was assessed using mathematical and simulation analyses.

Main Results:

• Cortisol half-lives differed significantly across models, with a notable model-group interaction.
• Model 4 demonstrated significantly reduced free cortisol half-life and improved data fit compared to Models 1-3.
• Model 4 exhibited superior overall model performance characteristics.

Conclusions:

• The proposed 4-compartment diffusion model (Model 4) aligns with experimental data and validation criteria.
• Model 4 provides generalizable cortisol half-life solutions across different groups and infusion methods.
• Model 4 represents a more accurate and robust approach to modeling cortisol disposition.