重症成人静脉输注对乙酰氨基酚及其代谢物的人群药代动力学建模和剂量优化。

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Kannan Sridharan, Mwila Mulubwa, Ali Mohamed Qader
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引用次数: 0

摘要

背景与目的:对乙酰氨基酚(扑热息痛)是危重患者普遍使用的药物。考虑到文献的缺乏,我们评估了静脉注射对乙酰氨基酚及其主要代谢物(硫酸盐和葡萄糖醛酸盐)在该人群中的人群药代动力学。方法:以静脉注射对乙酰氨基酚的危重成人为研究对象。每位患者抽取一至三份血样,用于评估对乙酰氨基酚及其代谢物(对乙酰氨基酚葡萄糖醛酸盐和对乙酰氨基酚硫酸盐)的含量。采用高效液相色谱法测定血清浓度。我们使用非线性混合效应模型来估计对乙酰氨基酚及其代谢物的主要药代动力学参数。利用蒙特卡罗模拟方法对协变量的影响进行了评价,并对剂量进行了优化。人口统计学信息、肝肾功能检查等患者因素作为人群药代动力学分析的协变量。对乙酰氨基酚的治疗范围为66 ~ 132 μM,毒性阈值为990 μM。结果:87名参与者被招募。一个联合的双室对乙酰氨基酚药代动力学模型与葡萄糖醛酸盐和硫酸盐代谢物室连接。中心和周边体积分布分别为7.87和8.87 L/70 kg。估计清除率(CL)为0.58 L/h/70 kg,而室间清除率为44.2 L/h/70 kg。葡萄糖醛酸盐和硫酸盐代谢产物CL分别为22和94.7 L/h/70 kg。蒙特卡罗模拟显示,每天两次给药对乙酰氨基酚会导致相对较高比例的患者达到并保持治疗范围内的血清浓度,浓度保持在毒性范围内的风险降低。结论:建立了重症患者静脉注射对乙酰氨基酚及其主要代谢物的联合药代动力学模型。对乙酰氨基酚CL在该患者群体中降低。我们建议减少给药频率,以减少在这一人群中出现超治疗浓度的风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults.

Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults.

Background and objective: Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population.

Methods: Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66-132 μM, while 990 μM was considered as the threshold for toxic concentration.

Results: Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70 kg, respectively. Estimated clearance (CL) was 0.58 L/h/70 kg, while intercompartmental clearance was 44.2 L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7 L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range.

Conclusion: A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.

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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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