Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis
Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis
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DOI：
10.1111/j.1460-9592.2005.01455.x
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发表时间：
2005-04-01
影响因子：
1.7
通讯作者：
Boccard, E
中科院分区：
文献类型：
--
作者：
Anderson, BJ;Pons, G;Boccard, E
背景资料：本研究的目的是描述丙帕他莫在儿童中的药代动力学，以预测丙帕他莫标准给药方案后的浓度30 mg.kg（-1）（15 mg/kg（-1）扑热息痛）6 h。扑热息痛时间-浓度曲线的群体药代动力学分析使用非线性混合效应模型（NONMEM）对144名儿童[受孕后年龄（PCA）27周-14岁]进行了846次观察。这些数据来自七项独立的研究，这些研究涉及静脉注射丙扑热息痛的儿童。时间-浓度曲线（503观察）从另外86名儿童（PCA：37周-14岁）给予扑热息痛酏剂口服纳入分析，以评估静脉propacetamol.Results的相对生物利用度：三室（贮库，中央和外周）线性处置模型拟合数据优于两室（贮库和中央）模型。群体参数估计值（受试者之间的变异性，%）为中央容积（V-2/F-口腔）24（55%）l。70 kg（-1），外周分布容积（V-3/F-口服）30（32%）l . 70 kg（-1），清除率（CL/F-口服）16（40%）l . h（-1）。70 kg（-1）和室间清除率（Q/F-口服）55（116%）l . h（-1）。70 kg（-1）。五氯苯甲醚清除率从27周（1.87 l.h（-1）70 kg（-1））增加到1岁时达到成熟值的84%（使用异速生长“1/4幂”模型标准化为70 kg的人）。外周分布容积从27周PCA（45.0 ± 1.70 kg（-1））下降到6月龄时达到其成熟值的110%。中心分布容积和室间清除率不随年龄变化。外周分布容积（V-3/F-经口）和清除率（CL/F-经口）的情况间变异性分别为18.5%和19.3%。丙氨酚水解为对乙酰氨基酚的速率常数（K-a 96 h（-1））与尺寸相关，但与年龄无关。与口服酏剂相比，静脉注射丙扑热息痛的相对生物利用度为0.5。结论：2-15岁儿童服用标准剂量丙扑热息痛6 h后，平均血清对乙酰氨基酚浓度为10 mg.l（-1）。mg.kg效应室中的该浓度与扁桃体切除术后2.6/10的疼痛减轻相关，并为轻度至中度疼痛提供令人满意的镇痛。在小于1岁的儿童中清除率降低，通过使用该年龄较小组的预测清除率调整该标准剂量方案，可以达到10 mg.l（-1）的目标浓度。
Background: The aim of this study was to describe propacetamol pharmacokinetics in children in order to predict concentrations after a standard dosing regimen of propacetamol 30 mg.kg(-1) (15 mg.kg(-1) paracetamol) 6 h.Methhods: A population pharmacokinetic analysis of paracetamol time-concentration profiles (846 observations) from 144 children [postconception age (PCA) 27 weeks-14 years] was undertaken using nonlinear mixed effects models (NONMEM). These data were taken from seven separate studies involving children given intravenous propacetamol. Time-concentration profiles (503 observations) from a further 86 children (PCA: 37 weeks-14 years) given paracetamol elixir orally were included in the analysis to assess relative bioavailability of intravenous propacetamol.Results: A three-compartment (depot, central and peripheral) linear disposition model fitted data better than a two-compartment (depot and central) model. Population parameter estimates (between subject variability, %) were central volume (V-2/F-oral) 24 (55%) l . 70 kg(-1), peripheral volume of distribution (V-3/F-oral) 30 (32%) l . 70 kg(-1), clearance (CL/F-oral) 16 (40%) l . h(-1) . 70 kg(-1) and intercompartment clearance (Q/F-oral) 55 (116%) l . h(-1) . 70 kg(-1). Clearance increased from 27 weeks PCA (1.87 l.h(-1) 70 kg(-1)) to reach 84% of the mature value by 1 year of age (standardized to a 70 kg person using allometric '1/4 power' models). Peripheral volume of distribution decreased from 27 weeks PCA (45.0 l.70 kg(-1)) to reach 110% of its mature value by 6 months of age. Central volume of distribution and intercompartment clearance did not change with age. Between occasions variability for the peripheral volume of distribution (V-3/F-oral) and clearance (CL/F-oral) were 18.5 and 19.3%, respectively. A rate constant representing hydrolysis of propacetamol to paracetamol (K-a 96 h(-1)) was size related, but not age related. The relative bioavailability of intravenous propacetamol compared with an oral elixir was 0.5.Conclusions: A mean paracetamol serum concentration of 10 mg.l(-1) is achieved in children 2-15 years given a standard dose of propacetamol 30 mg.kg(-1) 6 h. This concentration in the effect compartment is associated with a pain reduction of 2.6/10 after tonsillectomy and provides satisfactory analgesia for mild to moderate pain. Clearance is reduced in children less than 1 year of age and the target concentration of 10 mg.l(-1) may be achieved by scaling this standard dose regimen using predicted clearance in this younger age group.