Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Clin Pharmacol Ther. 2020 Nov;108(5):1098-1106. doi: 10.1002/cpt.1917. Epub 2020 Jun 27.
Drug dosing in encephalopathic neonates treated with therapeutic hypothermia is challenging; exposure is dependent on body size and maturation but can also be influenced by factors related to disease and treatment. A better understanding of underlying pharmacokinetic principles is essential to guide drug dosing in this population. The prospective multicenter cohort study PharmaCool was designed to investigate the pharmacokinetics of commonly used drugs in neonatal encephalopathy. In the present study, all data obtained in the PharmaCool study were combined to study the structural system specific effects of body size, maturation, recovery of organ function, and temperature on drug clearance using nonlinear mixed effects modeling. Data collected during the first 5 days of life from 192 neonates treated with therapeutic hypothermia were included. An integrated population pharmacokinetic model of seven drugs (morphine, midazolam, lidocaine, phenobarbital, amoxicillin, gentamicin, and benzylpenicillin) and five metabolites (morphine-3-glucuronide, morphine-6-glucuronide, 1-hydroxymidazolam, hydroxymidazolam glucuronide, and monoethylglycylxylidide) was successfully developed based on previously developed models for the individual drugs. For all compounds, body size was related to clearance using allometric relationships and maturation was described with gestational age in a fixed sigmoidal Hill equation. Organ recovery after birth was incorporated using postnatal age. Clearance increased by 1.23%/hours of life (95% confidence interval (CI) 1.03-1.43) and by 0.54%/hours of life (95% CI 0.371-0.750) for high and intermediate clearance compounds, respectively. Therapeutic hypothermia reduced clearance of intermediate clearance compounds only, by 6.83%/°C (95% CI 5.16%/°C-8.34%/°C). This integrated model can be used to facilitate drug dosing and future pharmacokinetic studies in this population.
治疗性低温治疗的脑病新生儿的药物剂量很具挑战性；药物暴露取决于体型和成熟度，但也可能受到与疾病和治疗相关的因素的影响。更好地了解潜在的药代动力学原理对于指导该人群的药物剂量非常重要。前瞻性多中心队列研究 PharmaCool 旨在研究新生儿脑病中常用药物的药代动力学。在本研究中，综合了 PharmaCool 研究中获得的所有数据，使用非线性混合效应模型研究了体型、成熟度、器官功能恢复和温度对药物清除率的结构性系统特异性影响。纳入了 192 名接受治疗性低温治疗的新生儿在生命的前 5 天的数据。成功地建立了七个药物（吗啡、咪达唑仑、利多卡因、苯巴比妥、阿莫西林、庆大霉素和苄青霉素）和五个代谢物（吗啡-3-葡糖苷酸、吗啡-6-葡糖苷酸、1-羟咪达唑仑、羟咪达唑仑葡糖苷酸和单乙基甘氨酰二甲脲）的综合群体药代动力学模型，该模型是基于之前开发的个体药物模型。对于所有化合物，使用比例关系与体型相关，使用胎龄的固定 sigmoidal Hill 方程描述成熟度。出生后器官恢复情况通过出生后年龄来体现。清除率每增加 1.23%/小时（95%置信区间（CI）1.03-1.43）和 0.54%/小时（95%CI 0.371-0.750），分别用于高清除率和中清除率化合物。治疗性低温仅降低中清除率化合物的清除率，降低 6.83%/°C（95%CI 5.16%/°C-8.34%/°C）。该综合模型可用于促进该人群的药物剂量和未来的药代动力学研究。
