Endocrine Abstracts

Background: Replacing physiological cortisol levels is important for the long-term health of patients with adrenal insufficiency and congenital adrenal hyperplasia (CAH). Modified-release formulations of hydrocortisone are one strategy being used to replace the cortisol circadian rhythm in adult patients but there is no data in children. Physiologically based pharmacokinetic (PBPK) modelling is a valuable tool for paediatric drug development¹; however, there are no examples of PBPK simulations for hormone replacement.

Objective: To develop a PBPK model for hydrocortisone.

Methodology: The PBPK model was developed using the Simcyp Simulator population-based PBPK software (Certara UK Ltd., UK; version 16.1). The model includes systems information to account for non-linear binding to cortisol binding protein, metabolism by 11β-HSD2 and 5α-reductase, and how these parameters develop with age. The model was developed and verified using published literature and cortisol pharmacokinetic data measured by LC-MS/MS in healthy adults and adults and children with CAH in trials of an immediate release formulation of hydrocortisone granules (Alkindi, Diurnal Ltd, UK) and a modified-release formulation of hydrocortisone (Chronocort, Diurnal Ltd, UK).

Results: The model predicted immediate-release hydrocortisone PK in adults across the dose range 0.5 to 20 mg, with predicted/observed AUCs within 0.8 to 1.25-fold – defined as a good prediction of the observed FDA bioequivalence criteria based on ± 20% difference - for both the published literature and test cohorts. The model predicted pharmacokinetic parameters for the modified-release formulation, with AUCs within 0.8 to 1.25-fold after single and multiple (representing an 8-hour interval between doses) dosing. After calculation of mg/kg and mg/m² modified-release doses roughly equivalent to 20 mg and 10 mg in adults, simulations were performed in a virtual paediatric population aged 12 to 18 years and results compared to equivalent doses simulated in adults. The results showed minimal difference in C_max, T_max, and AUCs between adults and adolescents.

Discussion: The PBPK model predicted PK parameters in adults and children acrosshydrocortisone dose ranges 0.5 to 20mg and captured the adult modified-release data after single and multiple dosing. Predictions in adolescents aged 12 to 18-years were aligned with current guidelines which recommend hydrocortisone dosing for adolescents with CAH of 10–15 mg/m² per day². This PBPK model will provide an invaluable tool in refining dosing regimens for patients who require hydrocortisone replacement therapy and allow prediction of dose for different populations and age groups.

References

1. Jamei M. Curr Pharmacol Rep 2016 2 161–9.

2. Speiser P. J Clin Endocrinol Metab 2018 103 4043–88.