A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy.

A joint model integrating endogenous ACTH and cortisol dynamics with hydrocortisone pharmacokinetics was successfully developed using a stepwise workflow.

• Data from 30 healthy volunteers was used for model development.
• The dataset included endogenous ACTH and cortisol concentrations without intervention as well as cortisol concentrations after dexamethasone suppression.
• Single dose hydrocortisone administrations of 0.5–10 mg as granules and 20 mg as granules and intravenous bolus were included.
• The model was developed by first building an endogenous ACTH and cortisol model, then merging it with a refined hydrocortisone pharmacokinetic model.

Time-dependent ACTH-driven endogenous cortisol production was quantified and implemented in the model.

• The model captured the circadian rhythm of cortisol production driven by ACTH.
• ACTH secretion exhibited a time-dependent morning peak that was explicitly characterized in the model.
• Cortisol-mediated feedback inhibition of ACTH secretion processes was also quantified and incorporated.

Cortisol-mediated negative feedback inhibition of ACTH secretion was quantified and incorporated into the HPA axis model.

• The feedback mechanism was identified as a key regulatory feature of the HPA axis.
• The model distinguished between feedback inhibition processes and time-dependent ACTH secretion drivers.
• This feedback was relevant to understanding how exogenous hydrocortisone interacts with the endogenous HPA axis.

Simulations demonstrated that hydrocortisone must be administered before the morning ACTH secretion peak to suppress ACTH overproduction in untreated CAH patients.

• Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals revealed the critical timing of hydrocortisone dosing.
• Untreated CAH patients showed ACTH overproduction due to impaired cortisol synthesis and consequent loss of feedback inhibition.
• The morning ACTH peak time was identified as a key reference point for optimizing hydrocortisone dosing schedules.
• Administration timing relative to the ACTH peak was shown to substantially affect the degree of ACTH suppression achieved.

The model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency.

• Simulations were performed with and without hydrocortisone administration in CAH patients.
• Varying degrees of enzyme deficiency (varying levels of cortisol synthesis impairment) were explored in the simulations.
• Healthy individual trajectories served as reference comparators for the CAH simulations.
• The framework enabled investigation of how different levels of adrenal insufficiency affect HPA axis dynamics.

The developed modeling framework provides a quantitative basis for optimizing cortisol replacement therapy in CAH.

• The framework integrated physiological mechanisms of HPA axis regulation with pharmacokinetic properties of hydrocortisone.
• The model paves the way towards cortisol replacement therapy optimization, as stated by the authors.
• Insights were gained on how hydrocortisone administration interacts with and perturbs the HPA axis in the context of CAH.
• The joint model can simulate the interplay between exogenous hydrocortisone and endogenous ACTH/cortisol dynamics.