Department of Pharmacy, Academic Medical Center, Amsterdam, The Netherlands
Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
Antimicrob Agents Chemother. 2018 Mar 27;62(4). doi: 10.1128/AAC.02311-17. Print 2018 Apr.
The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.
本研究旨在评估围产期窒息后行中重度低温治疗的足月新生儿群体中，静脉注射用苄星青霉素的药代动力学（PK）特性，因为目前尚不清楚该特性。本研究采用了一种特定于系统的建模方法，其中纳入了我们最近开发的描述同一患者研究人群中美罗培南清除率（CL）随发育和温度变化的协变量模型，以及基于出生体重（BW）的体表面积比例法对青霉素 G 的群体 PK 模型。描述药物消除随发育变化的儿科人群协变量模型可能构成特定于系统的信息，因此可纳入通过相同途径清除的药物的 PK 模型中。将该特定于系统的模型与参考模型的性能进行了比较。此外，还进行了 Monte-Carlo 模拟以评估最佳剂量。该特定于系统的模型与参考模型的性能相当。CL 与出生后年龄（PNA）、胎龄（GA）、体温（TEMP）、尿量（UO；特定于系统的模型）和多器官衰竭（参考模型）之间存在显著相关性。对于 GA 为 40 周、BW 为 3000g、PNA 为 2 天（TEMP，33.5°C）且 UO 正常（2ml/kg/h）的典型患者，在特定于系统的模型中，苄星青霉素 CL 为 0.48 升/小时（个体间变异性[IIV]为 49%），中央室分布容积为 0.62 升/千克（IIV 为 53%）。基于模拟结果，我们建议 GA 为 36-37 周、38-41 周和≥42 周的患者分别给予 75,000IU/kg/天 q8h、150,000IU/kg/天 q8h 和 200,000IU/kg/天 q6h 的静脉注射用苄星青霉素方案。该特定于系统的模型可用于其他通过相同途径清除的药物，从而加速模型开发。
