Pokorná Pavla, Michaličková Danica, Völler Swantje, Hronová Karolina, Tibboel Dick, Slanař Ondřej, Krekels Elke H
Department of Pediatrics and Inherited Metabolic Disorders, General University Hospital.
st Faculty of Medicine, Charles University, Prague, Czech Republic.
Minerva Pediatr (Torino). 2022 Apr;74(2):107-115. doi: 10.23736/S2724-5276.20.05740-0. Epub 2020 Oct 27.
The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia.
Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h.
Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital.
Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.
本研究采用群体建模方法，评估并量化窒息和缺氧缺血性脑病（HIE）的严重程度对接受治疗性低温治疗的窒息新生儿苯巴比妥药代动力学的影响。
纳入的新生儿接受了苯巴比妥治疗（TOBY试验方案）。从50名新生儿中获取了120份血浆样本，中位体重（四分位间距）为3.3（2.8 - 3.5）kg，胎龄为39（39 - 40）周。使用NONMEM 7.2版进行数据分析。将年龄、体重、性别、合并用药、肾和肝功能指标以及窒息和HIE的严重程度参数作为苯巴比妥药代动力学的潜在协变量进行测试。重度窒息定义为脐动脉血pH值≤7.1且1分钟阿氏评分≤5分，重度HIE定义为振幅整合脑电图（aEEG）恢复正常的时间>24小时。
发现体重是分布容积唯一具有统计学意义的协变量。体重为1 kg时分布容积为0.91 L，每增加1 kg，分布容积增加0.91 L。清除率为0.00563 L/h。没有协变量对苯巴比妥的清除率具有统计学意义。
在所研究的人群中，无论窒息或HIE的严重程度如何，均无需调整苯巴比妥剂量。
