The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep
The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep
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DOI：
10.3390/ijms21093042
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发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Bennet, Laura
中科院分区：
文献类型：
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作者：
Dhillon, Simerdeep K.;Wassink, Guido;Bennet, Laura
大剂量重组人促红细胞生成素（rEPO）是治疗早产儿和足月新生儿缺氧缺血性脑病（HIE）的一种有前途的潜在神经保护治疗方法。关于新生儿高剂量rEPO的药代动力学数据有限。我们研究了体重、胎龄、窒息、脑缺血、低温和外源性rEPO对胎羊大剂量rEPO药代动力学的影响。妊娠第129天（妊娠0.87天）（足月147天）的近足月胎羊接受假缺血（n = 5）或脑缺血30 min，然后用溶媒（n = 4）、rEPO（n = 8）或rEPO和低温联合治疗（n = 8）。妊娠第104天（妊娠0.7天）的早产胎羊接受假窒息（n = 1）或完全脐带闭塞25分钟，然后静脉输注溶媒（n = 8）或rEPO（n = 27）治疗。在早产和近足月胎儿中给予rEPO作为负荷推注，然后延长持续输注66至71.5小时。另一组早产胎羊接受rEPO重复推注（n = 8）。rEPO的血药浓度最好用一级和混合级消除模型描述，消除随孕龄线性成熟。治疗性低温、脑缺血、全窒息或外源性治疗对rEPO药代动力学无明显影响。随着孕龄的增加，rEPO的消除增加，这表明为了在长期治疗期间维持目标暴露水平，可能必须调整rEPO的剂量以匹配大小和生长的增加。这些结果对于设计和理解未来的高剂量rEPO神经保护研究具有重要意义。
High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (n = 5) or cerebral ischemia for 30 min followed by treatment with vehicle (n = 4), rEPO (n = 8) or combined treatment with rEPO and hypothermia (n = 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (n = 1) or complete umbilical cord occlusion for 25 min followed by i.v. infusion of vehicle (n = 8) or rEPO (n = 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5 h in preterm and near-term fetuses. A further group of preterm fetal sheep received repeated bolus injections of rEPO (n = 8). The plasma concentrations of rEPO were best described by a pharmacokinetic model that included first-order and mixed-order elimination with linear maturation of elimination with gestation age. There were no detectable effects of therapeutic hypothermia, cerebral ischemia, global asphyxia or exogenous treatment on rEPO pharmacokinetics. The increase in rEPO elimination with gestation age suggests that to maintain target exposure levels during prolonged treatment, the dose of rEPO may have to be adjusted to match the increase in size and growth. These results are important for designing and understanding future studies of neuroprotection with high-dose rEPO.