Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children

Abstract

<jats:p>Context: Accurate hydrocortisone dosing in children with adrenal insufficiency is important to avoid the risks of over and under treatment including iatrogenic Cushing`s syndrome and adrenal crisis. </jats:p> <jats:p>Objective: To establish a population pharmacokinetic model of hydrocortisone in children and use this to refine hydrocortisone replacement regimens. </jats:p> <jats:p>Design and methods: Pharmacokinetic study of hydrocortisone granules, available in 0.5, 1, 2 and 5 mg dose strengths, in 24 children with adrenal insufficiency aged 2 weeks to 6 years. Cortisol concentrations quantified by LC-MS/MS were used to refine an adult pharmacokinetic model to a paediatric population model which was then used to simulate 7 different hydrocortisone treatment regimens. </jats:p> <jats:p>Results: Pre-dose cortisol levels were undetectable in 54% of the 24 children. The developed pharmacokinetic model had good predictive performance. Simulations for the 7 treatment regimens using either three- or four-times daily dosing showed treatment regimens delivered an AUC24h within the 90% reference range for healthy children except in neonates where 2 regimens had an AUC below the 5th percentile. Cortisol concentrations at individual time points in the 24 hours were outside the 90% reference range for healthy individuals in 50%, 55% - 65% and 70% - 75% for children, infants and neonates, respectively, with low cortisol levels being most prevalent. </jats:p> <jats:p>Conclusions: Current paediatric hydrocortisone treatment regimens based on either three- or four-times daily administration replicate cortisol exposure based on AUC24h but the majority of cortisol levels are above or below physiological cortisol levels with low levels very common before the next dose.</jats:p>

Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis

“…To evaluate the applicability of DBS sampling, it is essential to understand the relationship between cortisol DBS concentrations, and plasma concentrations. Cortisol has complex PK with saturable binding to corticosteroid-binding globulin (CBG) and linear binding to albumin which previously has been identified using a nonlinear mixed-effects (NLME) HC PK model [( Melin et al, 2017 ; Michelet et al, 2020 )]. Moreover, cortisol is known to associate with RBCs ( Lentjes and Romijn, 1999 ).…”

Novel treatments for congenital adrenal hyperplasia

“…The current glucocorticoid substitution therapy that is established for patients with all forms of adrenal insufficiency has important limitations for CAH patients; conventional immediate-release glucocorticoid preparations fail to effectively suppress the HPA-axis that is necessary to suppress adrenal androgen production. Immediate-release formulations result in high glucocorticoid levels after each dose, that are potentially followed by a period of low levels of glucocorticoids after 4 -6 h [33][34][35], leading to periods of inefficient suppression of the HPA-axis and the need of higher glucocorticoids to achieve this goal.…”

“…-Short half-life may result in periods of undertreatment. [35,[37][38][39] -Allows accurate dosing (0.5, 1, 2, 5 mg).…”

Peri‐operative steroid management in the paediatric population

“…nal insufficiency is 10-15 mg/m 2 /d 48. With regard to cortisol stress response, cortisol response to ACTH stimulation tests has been shown to correlate well with cortisol response to surgery in the adult population and a stress response in adults is generally accepted as a cortisol of 500-600 nmol/L 1 h after appropriate stimulation (ACTH or insulin-induced hypoglycaemia testing) 36,43,[49][50]…”