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Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic

Johanna Melin1,2, Zinnia P Parra-Guillen1, Niklas Hartung1,3

  • 1Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr 31, 12169, Berlin, Germany.

Clinical Pharmacokinetics
|August 2, 2017
PubMed

Insights

Optimizing hydrocortisone replacement therapy for children is crucial. A new pharmacokinetic model for Infacort® helps predict accurate dosing for pediatric patients with adrenal insufficiency, especially those under 20 kg.

Area of Science:

  • Pharmacokinetics
  • Pediatric Endocrinology
  • Drug Development

Background:

  • Hydrocortisone replacement therapy in children lacks licensed formulations and doses in Europe for those under 6.
  • Hydrocortisone exhibits non-linear pharmacokinetics due to saturable plasma protein binding.
  • A new pediatric formulation, Infacort® oral hydrocortisone granules, has been developed.

Purpose of the Study:

  • To establish a population pharmacokinetic model for hydrocortisone.
  • To predict hydrocortisone exposure in pediatric patients with adrenal insufficiency.
  • To inform dosing strategies for a new pediatric hydrocortisone formulation.

Main Methods:

  • Evaluated cortisol and binding protein concentrations in healthy volunteers (n=30).
  • Utilized dexamethasone to suppress endogenous cortisol.
  • Developed a plasma protein binding model integrated into a pharmacokinetic model.

Main Results:

  • A two-compartment model with saturable absorption accurately described the data.
  • Both specific (non-linear) and non-specific (linear) protein binding were incorporated.
  • Predicted cortisol exposure varied significantly for individuals <20 kg.

Conclusions:

  • A semi-mechanistic pharmacokinetic model for hydrocortisone was developed.
  • The model simplifies complex hydrocortisone pharmacokinetics.
  • Accurate dosing is critical for neonates and infants <20 kg to mimic physiological concentrations.
Abstract

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