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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 4/2018

01-04-2018 | Original Research Article

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

Authors: Johanna Melin, Zinnia P. Parra-Guillen, Niklas Hartung, Wilhelm Huisinga, Richard J. Ross, Martin J. Whitaker, Charlotte Kloft

Published in: Clinical Pharmacokinetics | Issue 4/2018

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Abstract

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.
Appendix
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Metadata
Title
Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults
Authors
Johanna Melin
Zinnia P. Parra-Guillen
Niklas Hartung
Wilhelm Huisinga
Richard J. Ross
Martin J. Whitaker
Charlotte Kloft
Publication date
01-04-2018
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 4/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-017-0575-8

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