基于生理学的药代动力学模型
类阿片
医学
怀孕
药代动力学
胎儿
妊娠期
药理学
药品
作者
Matthijs W. van Hoogdalem,Scott L. Wexelblatt,Henry T. Akinbi,Alexander A. Vinks,Tomoyuki Mizuno
标识
DOI:10.1016/j.pharmthera.2021.108045
摘要
Physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to study pharmacokinetics (PK) in special populations, such as pregnant women, fetuses, and newborns, where practical hurdles severely limit the study of drug behavior. PK in pregnant women is variable and everchanging, differing greatly from that in their nonpregnant female and male counterparts typically enrolled in clinical trials. PBPK models can accommodate pregnancy-induced physiological and metabolic changes, thereby providing mechanistic insights into maternal drug disposition and fetal exposure. Fueled by the soaring opioid epidemic in the United States, opioid use during pregnancy continues to rise, leading to an increased incidence of neonatal opioid withdrawal syndrome (NOWS). The severity of NOWS is influenced by a complex interplay of extrinsic and intrinsic factors, and varies substantially between newborns, but the extent of prenatal opioid exposure is likely the primary driver. Fetomaternal PBPK modeling is an attractive approach to predict in utero opioid exposure. To facilitate the development of fetomaternal PBPK models of opioids, this review provides a detailed overview of pregnancy-induced changes affecting the PK of commonly used opioids during gestation. Moreover, the placental transfer of these opioids is described, along with their disposition in the fetus. Lastly, the implementation of these factors into PBPK models is discussed. Fetomaternal PBPK modeling of opioids is expected to provide improved insights in fetal opioid exposure, which allows for prediction of postnatal NOWS severity, thereby opening the way for precision postnatal treatment of these vulnerable infants.
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