Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4399, USA.
Br J Anaesth. 2013 May;110(5):788-99. doi: 10.1093/bja/aes507. Epub 2013 Jan 25.
Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery.
Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs.
Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively.
EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.
了解抗纤维蛋白溶酶 ε-氨基己酸（EACA）的临床药理学对于儿童合理用药至关重要。本研究旨在确定接受颅面重建手术的 6-24 个月龄婴儿的 EACA 药代动力学（PKs）。
连续纳入 6 名婴儿为一个队列，分别接受三种递增负荷剂量-持续静脉滴注（CIVI）方案之一：25mg/kg、10mg/kg/h；50mg/kg、20mg/kg/h；100mg/kg、40mg/kg/h。使用验证后的高效液相色谱-串联质谱测定法测定血浆 EACA 浓度。采用群体非线性混合效应模型方法来描述 EACA 的 PKs。
使用体重作为比例协变量和年龄效应的两室分布模型来估计 EACA 的群体 PK 参数。本研究中典型患者的年龄为 38.71 周，体重为 8.82kg。该典型患者的 PK 参数为：术前/术后血浆药物清除率为 32ml/min（3.6ml/kg/min），隔室清除率为 42.4ml/min（4.8ml/min/kg），中央分布容积为 1.27 升（0.14 升/kg），外周分布容积为 2.53 升（0.29 升/kg）。术中清除率和中央分布容积分别为术前/术后值的 89%和 80%。
EACA 清除率随体重和年龄增加而增加。清除率对体重的依赖性支持基于体重的给药方案。基于本研究，对于接受这些手术的 6-24 个月龄儿童，推荐负荷剂量 100mg/kg，随后 CIVI 剂量 40mg/kg/h，以维持目标血浆 EACA 浓度。
