Wiersma H E, van Boxtel C J, Butter J J, van Aalderen W M C, Omari T, Benninga M A
Department of Clinical Pharmacology & Pharmacotherapy, AMC, Amsterdam, The Netherlands.
Ther Drug Monit. 2003 Feb;25(1):93-8. doi: 10.1097/00007691-200302000-00014.
Transient relaxation of the lower esophageal sphincter (TLESR) is the predominant mechanism of gastroesophageal reflux (GER) in adults and children. Baclofen [4-amino-3-(p-chlorophenyl)-butanoic acid], a gamma-aminobutyric acid (GABA)-B receptor agonist used for the management of spasticity, has been recently shown to significantly inhibit GER in healthy adults without any relevant side effects. The objective of this study was to evaluate the pharmacokinetics of baclofen in a pediatric population with GER disease. In an open-label single-dose pharmacokinetic study, eight children with the diagnosis of GER made on clinical grounds received an oral dose of baclofen, 2.5 mg. Blood samples were drawn from an indwelling venous catheter, and urine was collected during a postdose period of 8 hours. The concentration of baclofen in these body fluids was determined using a validated high-performance liquid chromatography (HPLC) method with electrochemical detection after OPA-sulfite derivatization. Pharmacokinetic data were analyzed using the nonlinear regression program Scientist. Serum concentration-time curves could be best described using a two-compartment open model with a lag time. Mean plasma clearance (Cl) was 315.9 mL/h/kg; volume of distribution (Vd) was 2.58 L/kg; and half-life (T(1/2)beta) was 5.10 hours. No side effects were noted. As half-lives were comparable with those found in adult studies, the risk for accumulation seems not greater in children than in adults. Body composition can have a strong influence on the Vd of baclofen and, therefore, on the dose needed to obtain therapeutic plasma levels. Dosing according to clearly defined age groups with the help of therapeutic drug monitoring seems preferable. In view of the negative correlation between body weight and Vd, dosing according to body weight using adult pharmacokinetic data does not seem an effective way for using baclofen in children.
下食管括约肌短暂松弛（TLESR）是成人和儿童胃食管反流（GER）的主要机制。巴氯芬[4-氨基-3-（对氯苯基）-丁酸]是一种用于治疗痉挛的γ-氨基丁酸（GABA）-B受体激动剂，最近已证明它能显著抑制健康成年人的GER，且无任何相关副作用。本研究的目的是评估巴氯芬在患有GER疾病的儿科人群中的药代动力学。在一项开放标签单剂量药代动力学研究中，八名根据临床诊断为GER的儿童口服了2.5毫克巴氯芬。从留置的静脉导管采集血样，并在给药后8小时内收集尿液。使用经过验证的高效液相色谱（HPLC）方法，在OPA-亚硫酸盐衍生化后通过电化学检测来测定这些体液中巴氯芬的浓度。使用非线性回归程序Scientist分析药代动力学数据。血清浓度-时间曲线可用具有滞后时间的二室开放模型来最佳描述。平均血浆清除率（Cl）为315.9毫升/小时/千克；分布容积（Vd）为2.58升/千克；半衰期（T(1/2)β）为5.10小时。未观察到副作用。由于半衰期与成人研究中的结果相当，儿童中药物蓄积的风险似乎并不比成人更大。身体组成可能对巴氯芬的Vd有很大影响，因此也会对获得治疗性血浆水平所需的剂量产生影响。借助治疗药物监测，根据明确界定的年龄组给药似乎更为可取。鉴于体重与Vd之间呈负相关，使用成人药代动力学数据根据体重给药似乎不是在儿童中使用巴氯芬的有效方法。
