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

Clin Pharmacokinet. 2018 Apr;57(4):515-527. doi: 10.1007/s40262-017-0575-8.


Background and objective: Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort® oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency.

Methods: Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort® or 20 mg of Infacort®/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model.

Results: Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline cort,15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing <20 kg.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Adrenal Insufficiency / blood
  • Adrenal Insufficiency / diagnosis
  • Adrenal Insufficiency / drug therapy*
  • Adult
  • Age Factors
  • Child, Preschool
  • Computer Simulation
  • Drug Compounding
  • Drug Dosage Calculations
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / blood
  • Glucocorticoids / pharmacology*
  • Hormone Replacement Therapy / methods*
  • Humans
  • Hydrocortisone / administration & dosage
  • Hydrocortisone / blood
  • Hydrocortisone / pharmacokinetics*
  • Infant
  • Infant, Newborn
  • Middle Aged
  • Models, Biological*
  • Protein Binding
  • Randomized Controlled Trials as Topic
  • Young Adult


  • Glucocorticoids
  • Hydrocortisone