AstraZeneca, Södertälje, Sweden.
Clin Ther. 2012 Aug;34(8):1828-38. doi: 10.1016/j.clinthera.2012.06.028. Epub 2012 Jul 24.
Several oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children.
The aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children.
In this multicenter, open-label study, hospitalized patients (0-17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0-1 month of age), 1.0 mg/kg (1-11 months of age), 10 mg (1-5 years of age), 10 or 20 mg (6-11 years of age), or 20 or 40 mg (12-17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed.
Fifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC(τ) ranged from 6.9 μmol · h/L (10 mg, 6-11 years) to 17.6 μmol · h/L (40 mg, 12-17 years). The mean C(ss,max) ranged from 3.7 μmol/L (0.5 mg/kg, 0-1 month) to 10.5 μmol/L (40 mg, 12-17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs.
Intravenous esomeprazole at doses resulting in targeted AUC(τ) and C(ss,max) similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019.
目前，几种口服质子泵抑制剂（PPIs）已在北美和欧洲获得批准用于儿科患者。然而，当口服治疗不可行或不适当时，PPI 的静脉制剂可能会有所帮助。在美国，静脉注射艾司奥美拉唑获批用于治疗成人和 1 个月至 17 岁（含）的儿科患者的短期治疗胃食管反流病（GERD）伴糜烂性食管炎，可替代口服治疗。四项在 GERD 成人患者中开展的开放性、随机、2 向交叉研究发现，口服和静脉注射艾司奥美拉唑重复给药之间在胃酸抑制方面无临床相关差异。然而，尚未在儿童中广泛研究静脉内艾司奥美拉唑的药代动力学。
本研究旨在评估儿童重复静脉内艾司奥美拉唑给药的稳态药代动力学和耐受性。
在这项多中心、开放性研究中，考虑进行酸抑制治疗的住院患者（0-17 岁）接受为期 4 天的每日一次静脉内艾司奥美拉唑钠注射剂 0.5 mg/kg（0-1 个月龄）、1.0 mg/kg（1-11 个月龄）、10 mg（1-5 岁）、10 或 20 mg（6-11 岁）或 20 或 40 mg（12-17 岁）治疗。6-11 岁（含）的儿童以 1:1 的比例随机接受艾司奥美拉唑 10 或 20 mg，12-17 岁（含）的青少年以 1:1 的比例随机接受艾司奥美拉唑 20 或 40 mg。给药前和给药后采集血样。使用反相液相色谱和质谱法测量血浆艾司奥美拉唑。使用混合效应模型得出药代动力学变量。评估不良事件（AE）。
59 名患者被随机分组，57 名患者接受了研究药物。大多数患者为白人（44 名白人、5 名黑人/非裔美国人、3 名亚洲人、5 名其他人）和男性（35/57）。50 名患者有资格进行药代动力学分析，每个年龄组包括 6-8 名患者。艾司奥美拉唑的药代动力学呈剂量比例关系，并与体重和年龄相关。清除率随体重和年龄的增加而增加。AUC（τ）的平均值范围为 6.9 μmol·h/L（10 mg，6-11 岁）至 17.6 μmol·h/L（40 mg，12-17 岁）。C（ss，max）的平均值范围为 3.7 μmol/L（0.5 mg/kg，0-1 个月）至 10.5 μmol/L（40 mg，12-17 岁）。31 名患者出现 1 次或多次 AE；6 名患者出现 1 次或多次与治疗无关的严重 AE。
在本小样本、选择性儿科人群中，静脉内艾司奥美拉唑的剂量可使 AUC（τ）和 C（ss，max）达到与成人治疗相关的目标水平，似乎具有良好的耐受性。临床试验注册编号：NCT00474019。
