Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data

Author(s): Karina Claassen, Kirstin Thelen, Katrin Coboeken, Thomas Gaub, Jorg Lippert, Karel Allegaert, Stefan Willmann.

Journal Name: Current Pharmaceutical Design

Volume 21 , Issue 39 , 2015

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Abstract:

Among pediatric patients, preterm neonates and newborns are the most vulnerable subpopulation. Rapid developmental changes of physiological factors affecting the pharmacokinetics of drug substances in newborns require extreme care in dose and dose regimen decisions. These decisions could be supported by in silico methods such as physiologically-based pharmacokinetic (PBPK) modeling. In a comprehensive literature search, the physiological information of preterm neonates that is required to establish a PBPK model has been summarized and implemented into the database of a generic PBPK software. Physiological parameters include the organ weights and blood flow rates, tissue composition, as well as ontogeny information about metabolic and elimination processes in the liver and kidney. The aim of this work is to evaluate the model’s accuracy in predicting the pharmacokinetics following intravenous administration of two model drugs with distinct physicochemical properties and elimination pathways based on earlier reported in vivo data. To this end, PBPK models of amikacin and paracetamol have been set up to predict their plasma levels in preterm neonates. Predicted plasma concentration-time profiles were compared to experimentally obtained in vivo data. For both drugs, plasma concentrationtime profiles following single and multiple dosing were appropriately predicted for a large range gestational and postnatal ages. In summary, PBPK simulations in preterm neonates appear feasible and might become a useful tool in the future to support dosing decisions in this special patient population.

Keywords: Physiology, preterm, newborn, maturation, pharmacokinetic, amikacin, paracetamol.

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Article Details

VOLUME: 21
ISSUE: 39
Year: 2015
Page: [5688 - 5698]
Pages: 11
DOI: 10.2174/1381612821666150901110533
Price: $58

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