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Project

I-PREDICT: Innovative Physiology-based pharmacokinetic model to pREdict Drug exposure In neonates undergoing Cooling Therapy

Drug disposition in neonates depends on maturational and non-maturational covariates. We hypothesize that cooling, a standard therapy for asphyxiated neonates with hypoxic-ischemic encephalopathy, is such a non-maturational covariate. The main goal of the project is to develop an innovative physiology-based pharmacokinetic (PBPK) framework to describe and predict the impact of cooling on drug disposition in asphyxiated neonates. PBPK models combine drug-specific data with physiological data of a population of interest to guide drug dosing. The effect of cooling on drug metabolism is hereby defined as a knowledge gap. Using a multidisciplinary approach, in vitro, animal experimental and human data will be collected for development of the model. First, the impact of temperature on expression and function of drug metabolizing enzymes (DME) and drug transporters (DT) will be assessed in vitro on human and porcine hepatocytes. Second, the utility of endogenous biomarkers reflecting  DME and DT activity during cooling is investigated. Third, the results will be used to build PBPK  models for selected drugs. Finally, in vivo PK data in human asphyxiated neonates undergoing cooling and in an experimental in vivo setting of neonatal minipigs will be used to evaluate the models. The outcome will be drug dose prediction and drug development in neonates undergoing cooling. The framework may also be applied to develop temperature driven PBPK-models in other special populations.

Date:1 Jan 2020 →  31 Dec 2023
Keywords:physiology-based pharmacokinetic (PBPK) framework, asphyxiated neonates, hypoxic-ischemic encephalopathy, cooling therapy
Disciplines:Neonatology, Pharmacotherapy, Pharmacokinetics, Biomarker evaluation