Development and verification of an endogenous PBPK model to inform hydrocortisone replacement dosing in children and adults with cortisol deficiency.

Autor: Bonner JJ; Certara UK Limited, Simcyp Division, Sheffield, UK. Electronic address: Jennifer.Bonner@certara.com., Burt H; Certara UK Limited, Simcyp Division, Sheffield, UK., Johnson TN; Certara UK Limited, Simcyp Division, Sheffield, UK., Whitaker MJ; University of Sheffield, Sheffield, UK; Diurnal Limited, Cardiff, UK., Porter J; Diurnal Limited, Cardiff, UK., Ross RJ; University of Sheffield, Sheffield, UK; Diurnal Limited, Cardiff, UK.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2021 Oct 01; Vol. 165, pp. 105913. Date of Electronic Publication: 2021 Jun 17.
DOI: 10.1016/j.ejps.2021.105913
Abstrakt: The goal of hormone replacement is to mirror physiology. Hydrocortisone granules and modified release formulations are being developed to optimise cortisol replacement in the rare disease of adrenal insufficiency. To facilitate clinical development, we built and verified a physiologically based pharmacokinetic (PBPK) model for the endogenous hormone cortisol (hydrocortisone) in healthy adults, and children and adults with adrenal insufficiency. The model predicted immediate-release hydrocortisone pharmacokinetics in adults across the dose range 0.5 to 20 mg, with predicted/observed AUCs within 0.8 to 1.25-fold.  The model also tightly predicted pharmacokinetic parameters for modified-release formulations, with AUCs within 0.8 to 1.25-fold after single and multiple dosing.  Predicted modified-release formulation pharmacokinetics (PK) in 12 to 18-year olds showed PK to be similar to adults. This hydrocortisone PBPK model is a useful tool to predict adult and paediatric pharmacokinetics of both immediate- and modified-release hydrocortisone formulations, and develop clinical dosing regimens.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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