McAdams Ryan M, Pak Daniel, Lalovic Bojan, Phillips Brian, Shen Danny D
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Pharmacy, Seattle Children's Hospital, Seattle, WA, USA.
Anesthesiol Res Pract. 2020 Feb 25;2020:2582965. doi: 10.1155/2020/2582965. eCollection 2020.
Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 g/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.
右美托咪定是一种很有前景的镇静镇痛药，适用于接受治疗性低温（TH）的缺氧缺血性脑病（HIE）新生儿。在一项I期单中心开放标签研究中评估了右美托咪定的药代动力学和安全性，为未来的试验策略提供依据。我们招募了7名胎龄≥36周、诊断为中重度HIE的新生儿，他们在TH及6小时复温期接受右美托咪定持续输注。在64.8±6.9小时输注期间及之后，通过连续采血来表征血浆右美托咪定浓度的时间过程。非房室分析得出描述性药代动力学估计值：血浆清除率为0.760±0.155L/h/kg，稳态分布容积为5.22±2.62L/kg，平均驻留时间为6.84±3.20小时。根据一室模型进行的初始汇总分析和群体分析得出了相似的清除率和分布容积估计值。总体而言，与先前报道的在可比胎龄和月经后年龄的未接受低温治疗（体温正常）且无HIE的新生儿相比，接受低温治疗的HIE新生儿的清除率相当或更低，分布容积更大，平均驻留时间或消除半衰期更长。因此，与基于无HIE的体温正常新生儿报道的药代动力学参数预测的浓度-时间曲线相比，接受低温治疗的HIE新生儿在输注最初几小时血浆浓度上升更缓慢，而稳态水平相似。右美托咪定治疗未出现急性不良事件。虽然右美托咪定在输注剂量高达0.4μg/kg/h时对接受TH的HIE新生儿似乎是安全的，但可能需要采用负荷剂量策略来克服血浆右美托咪定浓度上升的初始延迟。
