Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults
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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.
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.
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.
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.
The authors would like to thank the high-performance computing service of ZEDAT, Freie Universitaet Berlin, for computing time. In addition, the authors would like to thank Trevor Johnson and Dena Digweed for valuable support. Parts of the results were presented as a poster at the 2016 Population Approach Group Europe (PAGE) meeting.
Compliance with Ethical Standards
The work was carried out under a Cooperation Agreement between Freie Universitaet and Diurnal funded by the European Commission FP7 Grant (No. 281654 TAIN).
Conflict of interest
Johanna Melin, Zinnia P. Parra Guillen and Niklas Hartung have no conflicts of interest. Richard Ross is a director of Diurnal Ltd and has stock options. Martin Whitaker is an employee and director of Diurnal Ltd and has stock options. Charlotte Kloft reports a research grant to Freie Universitaet Berlin from Diurnal funded by the European Commission FP7 Grant (No. 281654 TAIN) and grants from the Innovative Medicines Initiative-Joint Undertaking (‘DDMoRe’). Charlotte Kloft and Wilhelm Huisinga report grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd, Merck KGaA and SANOFI).
Data from two studies (Registered EudraCT numbers: 2013-000260-28 and 2013-000259-42) were used for this analysis. Both studies were approved by the South East Wales Research Ethics committee and performed according to the 1964 Helsinki Declaration and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines.
Informed consent was obtained from all individual participants included in the study.
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