Melin, J., Parra-Guillen, Z.P., Hartung, N. et al. (4 more authors) (2018) Predicting cortisol exposure from paediatric hydrocortisone formulation using a semi-mechanistic pharmacokinetic model established in healthy adults. Clinical Pharmacokinetics, 57. pp. 515-527. ISSN 0312-5963
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.
Metadata
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Copyright, Publisher and Additional Information: | © Springer International Publishing AG 2017. | ||||
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals | ||||
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 11 Apr 2019 09:27 | ||||
Last Modified: | 11 Apr 2019 09:27 | ||||
Status: | Published | ||||
Publisher: | Springer Verlag | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1007/s40262-017-0575-8 |