Journal
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
Volume 19, Issue 7, Pages 461-477Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/17425255.2023.2237412
Keywords
Gottingen minipig; neonatal pathophysiology; perinatal asphyxia; pharmacotherapy; physiologically-based pharmacokinetic modeling; PBPK; therapeutic hypothermia; >
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Perinatal asphyxia (PA) continues to have significant morbidity and mortality rates. Therapeutic hypothermia (TH) is the only effective treatment for neonates with moderate to severe hypoxic-ischemic encephalopathy after PA. Additional pharmacotherapy may be necessary for these neonates, and both PA and TH can affect physiology and, consequently, pharmacokinetics (PK) and pharmacodynamics (PD).
IntroductionPerinatal asphyxia (PA) still causes significant morbidity and mortality. Therapeutic hypothermia (TH) is the only effective therapy for neonates with moderate to severe hypoxic-ischemic encephalopathy after PA. These neonates need additional pharmacotherapy, and both PA and TH may impact physiology and, consequently, pharmacokinetics (PK) and pharmacodynamics (PD).Areas coveredThis review provides an overview of the available knowledge in PubMed (until November 2022) on the pathophysiology of neonates with PA/TH. In vivo pig models for this setting enable distinguishing the effect of PA versus TH on PK and translating this effect to human neonates. Available asphyxia pig models and methodological considerations are described. A summary of human neonatal PK of supportive pharmacotherapy to improve neurodevelopmental outcomes is provided.Expert opinionTo support drug development for this population, knowledge from clinical observations (PK data, real-world data on physiology), preclinical (in vitro and in vivo (minipig)) data, and molecular and cellular biology insights can be integrated into a predictive physiologically-based PK (PBPK) framework, as illustrated by the I-PREDICT project (Innovative physiology-based pharmacokinetic model to predict drug exposure in neonates undergoing cooling therapy). Current knowledge, challenges, and expert opinion on the future directions of this research topic are provided.
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