Development and applications of a physiologically-based model of paediatric oral drug absorption.

Autor: Johnson TN; Simcyp Limited (a Certara company), Sheffield, UK. Electronic address: trevor.johnson@certara.com., Bonner JJ; Simcyp Limited (a Certara company), Sheffield, UK., Tucker GT; Emeritus Professor of Clinical Pharmacology, University of Sheffield, Sheffield, UK., Turner DB; Simcyp Limited (a Certara company), Sheffield, UK., Jamei M; Simcyp Limited (a Certara company), Sheffield, UK.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2018 Mar 30; Vol. 115, pp. 57-67. Date of Electronic Publication: 2018 Jan 05.
DOI: 10.1016/j.ejps.2018.01.009
Abstrakt: There is increasing interest in paediatric drug absorption and the development of biopharmaceutics tools to facilitate the development of oral formulations for neonates, infants and children. We describe the development and application of a physiologically-based model of paediatric drug absorption applicable from full term birth onwards. Paediatric age-specific parameters were included for salivary flow, gastric pH, gastric emptying (and associated food effects) and duodenal bile salt concentrations and the associated algorithms were integrated into a dissolution, absorption and metabolism model as part of a PBPK platform. For other parameters, there was either evidence for no age-related changes or a lack of data, so that adult values were applied. An initial assessment of the model was carried out by simulating the oral absorption of theophylline, paracetamol and ketoconazole over a range of paediatric ages. The absorption of the first two drugs, both BCS class 1 compounds, was predicted to be slower in early neonates compared to older age groups (median t max values of 3 vs 2h, respectively), but with invariant fraction absorbed (fa). This is in agreement with clinical observations. The t max of ketoconazole, a BCS class 2 compound, was predicted to be about 1h in both neonates and adults, but the fa value was higher in the former (0.87 vs 0.69). There is clearly a need to expand the components of the model as new information on the ontogeny of GI tract parameters becomes available, and to assess it against more in vivo data with evidence of specific age-related changes in oral drug absorption.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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