Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults

Abstract

Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing <20 kg. EudraCT number: 2013-000260-28, 2013-000259-42.

The circadian rhythm of corticosteroid‐binding globulin has little impact on cortisol exposure after hydrocortisone dosing

“…A total number of 350 CBG concentrations from a previously published study (ClinicalTrials.gov identifier: NCT01960530) with healthy volunteers were used for this analysis. The study was approved by the South East Wales Research Ethics committee and performed according to local and international guidelines (ICH guideline for good clinical practice and the Declaration of Helsinki).…”

“…By using a modelling and simulation approach, we aimed to systematically evaluate the impact on cortisol exposure (AUC and C max of total cortisol) of changing CBG concentrations. In order to do so, the predicted CBG concentrations based on the above described CBG model was linked to a previously published semi‐mechanistic pharmacokinetic (PK) model for hydrocortisone (using a novel paediatric hydrocortisone formulation with taste masking). The PK model consisted of a two‐compartment disposition model with saturable absorption (Michaelis‐Menten absorption) and a plasma protein binding model.…”

“…The binding model considered both the nonlinear binding to CBG—predicted by the circadian model—and linear binding to albumin or erythrocytes. More details regarding the semi‐mechanistic PK model for hydrocortisone can be found in Melin et al…”

“…In scenario 2, cortisol concentration‐time profiles were simulated using the established semi‐mechanistic PK model assuming either circadian (N = 100) or constant (N = 100) CBG profiles, respectively. AUC from dosing to 8 hours postdose (AUC 0‐8 hours ) and C max for cortisol were derived in the population with circadian (AUC circ , C max,circ ) and constant (AUC const , C max,const ) CBG concentrations assuming a recommended thrice daily dosing (10 mg at 06:00, 5 mg at 14:00 and 5 mg at 22:00) for adults .…”

“…Since only total cortisol concentrations were considered in the current work so far, the pharmacokinetic model was used to predict the free, that is unbound, cortisol concentration and free cortisol fraction for total cortisol concentrations ranging to the upper confidence level for C max after administration of 20 mg hydrocortisone (~900 nmol/L) for the minimum (median) and maximum (median) CBG concentrations observed over 24 hours in the current population.…”