Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia
Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia
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DOI：
10.1111/jpi.12565
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发表时间：
2019-05-01
影响因子：
10.3
通讯作者：
Buonocore, Giuseppe
中科院分区：
文献类型：
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作者：
Balduini, Walter;Weiss, Michael D.;Buonocore, Giuseppe
新生儿缺氧缺血性脑病（HIE）经低温治疗后，应用褪黑激素进行持续治疗可能是有益的。然而，褪黑激素的安全性，药代动力学（PK），剂量在这个敏感的population.Methods和resultsThis研究评估褪黑激素肠内给药的PK和安全性新生儿缺氧缺血性脑病进行低温。对5例HIE新生儿在低温治疗中按0.5mg/kg剂量输注褪黑素。在新生儿达到目标体温33.5 ℃后1小时开始输注。在褪黑激素输注前和输注后的选择时间收集血液样品。腹部并发症或患者的生命体征的临床显着变化没有发现期间或后褪黑激素。血浆峰浓度达到0.25 μ g/mL。在24小时的曲线下面积为4.35 μ g/mL*h。DiscussionMelatonin半衰期和清除率延长，分布容积下降相比，成人。计算机模拟估计在四次输注后可达到稳态。低温不影响褪黑激素PK。与动物实验相比，在人体中可以用较低剂量达到高血药浓度，尽管建议在新生儿人群中静脉给药。我们的研究是一个准备步骤，为未来的临床研究，旨在评估褪黑激素在HIE的疗效。
IntroductionNeonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population are still unknown.Methods and resultsThis study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1hour after the neonates reached the target temperature of 33.5 degrees C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients' vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 mu g/mL. The area under the curve in 24hours was 4.35 mu g/mL*h.DiscussionMelatonin half-life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE.