1. Development and verification of an endogenous PBPK model to inform hydrocortisone replacement dosing in children and adults with cortisol deficiency
- Author
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Trevor N. Johnson, Howard Burt, John Porter, Martin J. Whitaker, Richard J. Ross, and Jennifer J. Bonner
- Subjects
Adult ,Physiologically based pharmacokinetic modelling ,Hydrocortisone ,Rotation ,Hormone Replacement Therapy ,Pharmaceutical Science ,Endogeny ,02 engineering and technology ,Pharmacology ,Multiple dosing ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Adrenal insufficiency ,Humans ,Medicine ,Congenital adrenal hyperplasia ,Dosing ,Child ,business.industry ,021001 nanoscience & nanotechnology ,medicine.disease ,Area Under Curve ,0210 nano-technology ,business ,Adrenal Insufficiency ,medicine.drug - Abstract
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.
- Published
- 2021
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