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Title
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Integrated approaches in pediatric pharmacotherapy : the neonatal Göttingen minipig model for drug disposition in perinatal asphyxia and therapeutic hypothermia
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Author
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Abstract
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| Pediatric drug therapy presents challenges due to the pronounced growth and development during early life stages, affecting drug response. Perinatal asphyxia (PA) is a condition in neonates often requiring therapeutic hypothermia (TH) and intensive care to reduce morbidity and mortality. Animal models, such as the neonatal Göttingen Minipig, are valuable for understanding the mechanisms of conditions and therapies. This study hypothesized that systemic hypoxia, as well as TH, affect drug disposition, including enzyme functionality. The primary hypothesis was that TH significantly decreases metabolic clearance (CL) in asphyxiated neonates, necessitating drug dosing adjustments. To address this, in vitro and in vivo data from neonatal Göttingen Minipigs will be used to develop a physiologically-based pharmacokinetic (PBPK) model to ensure accurate drug dosing for asphyxiated neonates. An experimental study was carried out to examine the pharmacokinetics of midazolam, fentanyl, phenobarbital, and topiramate under four conditions: therapeutic hypothermia (group TH), hypoxia (group H), hypoxia and therapeutic hypothermia (group H+TH), and controls (group C). Six healthy male Göttingen Minipigs, within 24 hours of birth per condition, were anesthetized for drug administration and blood sampling. Whole-body hypothermia was induced by lowering the body temperature to 33.5C, while systemic hypoxia was induced using a low-oxygen gas mixture. The gene and protein expression, as well as the activity of cytochrome P450 (CYP) enzymes were evaluated using in vitro methods. The study confirmed the feasibility of conducting complex in vivo procedures in neonatal Göttingen Minipigs. Furthermore, a novel pig model of asphyxia was established. Fentanyl was mostly affected since TH led to a 66% decrease in CL and approximately a 3-fold longer half-life. The study also revealed TH impact on heart rate in neonatal Göttingen Minipigs, consistent with documented effects in human neonates. These effects are particularly important for high extraction ratio drugs like fentanyl, due to their dependence on liver blood flow for their subsequent metabolism. Additionally, the research provided insights into the influence of age, hypothermia, and hypoxia on CYP enzymes. The vitro studies revealed differences in CYP expression and activity between neonatal and adult Göttingen Minipigs, underscoring the role of maturation in drug metabolism. Additionally, adult liver microsomes exhibited a 36% reduction in CYP activity following in vitro hypothermia. Alterations in the expression of CYP3A29 and CYP2E1 occurred due to hypoxia in neonatal Göttingen Minipigs. Lastly, this PhD thesis underscores the importance of refining and updating PBPK models to improve its predictive accuracy and clinical relevance. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Veterinary Sciences
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2024
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DOI
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10.63028/10067/2100480151162165141
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Volume/pages
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227 p.
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Note
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Van Cruchten, Steven [Supervisor]
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Annaert, Pieter [Supervisor]
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Allegaert, Karel [Supervisor]
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Smits, Anne [Supervisor]
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Full text (open access)
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