癫痫患者左乙拉西坦的人群药代动力学和剂量模拟:肾功能和苯妥英联合给药的影响。

IF 2.3 4区 医学
Noppaket Singkham, Apinya Boonpeng, Pasiri Sithinamsuwan, Juthathip Suphanklang
{"title":"癫痫患者左乙拉西坦的人群药代动力学和剂量模拟:肾功能和苯妥英联合给药的影响。","authors":"Noppaket Singkham, Apinya Boonpeng, Pasiri Sithinamsuwan, Juthathip Suphanklang","doi":"10.1002/jcph.70101","DOIUrl":null,"url":null,"abstract":"<p><p>Levetiracetam (LEV) exhibits considerable interindividual pharmacokinetic variability; however, data in Thai populations remain limited. This study aimed to develop a population pharmacokinetic model of LEV, identify covariates affecting clearance, and inform individualized dosing strategies. A total of 374 LEV plasma concentrations from 264 Thai patients with epilepsy were analyzed using nonlinear mixed-effects modeling. The median age was 65.3 years (range 18.09-97.71). LEV pharmacokinetics was characterized by a one-compartment model with first-order elimination and proportional residual variability. The typical apparent clearance and volume of distribution were estimated at 2.61 L/h and 56.3 L, respectively. Clearance was significantly influenced by creatinine clearance (CrCL), estimated using the Cockcroft-Gault equation with adjusted body weight, and by phenytoin co-administration. Phenytoin increased clearance by 43.1%, while reduced CrCL was associated with lower clearance. Monte Carlo simulations demonstrated that both trough concentrations and the probability of achieving therapeutic targets (12-46 mg/L) declined with increasing CrCL, especially in patients receiving phenytoin. Standard 12-h dosing was generally sufficient for patients with impaired renal function who were not receiving phenytoin. In contrast, subtherapeutic exposure was more frequent in those with preserved or augmented renal function, particularly when phenytoin was co-administered. These findings support the use of higher or more frequent dosing in these subgroups. The final model provides a framework for individualized LEV dosing. Prospective studies are needed to validate these findings and guide their implementation in clinical practice.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Population Pharmacokinetics and Dose Simulation of Levetiracetam in Patients with Epilepsy: Influence of Renal Function and Phenytoin Co-Administration.\",\"authors\":\"Noppaket Singkham, Apinya Boonpeng, Pasiri Sithinamsuwan, Juthathip Suphanklang\",\"doi\":\"10.1002/jcph.70101\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Levetiracetam (LEV) exhibits considerable interindividual pharmacokinetic variability; however, data in Thai populations remain limited. This study aimed to develop a population pharmacokinetic model of LEV, identify covariates affecting clearance, and inform individualized dosing strategies. A total of 374 LEV plasma concentrations from 264 Thai patients with epilepsy were analyzed using nonlinear mixed-effects modeling. The median age was 65.3 years (range 18.09-97.71). LEV pharmacokinetics was characterized by a one-compartment model with first-order elimination and proportional residual variability. The typical apparent clearance and volume of distribution were estimated at 2.61 L/h and 56.3 L, respectively. Clearance was significantly influenced by creatinine clearance (CrCL), estimated using the Cockcroft-Gault equation with adjusted body weight, and by phenytoin co-administration. Phenytoin increased clearance by 43.1%, while reduced CrCL was associated with lower clearance. Monte Carlo simulations demonstrated that both trough concentrations and the probability of achieving therapeutic targets (12-46 mg/L) declined with increasing CrCL, especially in patients receiving phenytoin. Standard 12-h dosing was generally sufficient for patients with impaired renal function who were not receiving phenytoin. In contrast, subtherapeutic exposure was more frequent in those with preserved or augmented renal function, particularly when phenytoin was co-administered. These findings support the use of higher or more frequent dosing in these subgroups. The final model provides a framework for individualized LEV dosing. Prospective studies are needed to validate these findings and guide their implementation in clinical practice.</p>\",\"PeriodicalId\":48908,\"journal\":{\"name\":\"Journal of Clinical Pharmacology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/jcph.70101\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/jcph.70101","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

左乙拉西坦(LEV)表现出相当大的个体间药代动力学变异性;然而,泰国人口的数据仍然有限。本研究旨在建立LEV的人群药代动力学模型,确定影响清除率的协变量,并为个体化给药策略提供信息。采用非线性混合效应模型分析264例泰国癫痫患者374例LEV血浆浓度。年龄中位数为65.3岁(18.09-97.71)。LEV药代动力学采用一阶消除和比例剩余变异的单室模型表征。典型的表观间隙和分布体积分别为2.61 L/h和56.3 L。清除率受肌酐清除率(CrCL)和苯妥英联合给药的显著影响,前者使用校正体重的Cockcroft-Gault方程估算。苯妥英可使清除率提高43.1%,而降低的CrCL与较低的清除率相关。蒙特卡罗模拟表明,谷浓度和达到治疗目标(12-46 mg/L)的概率随着CrCL的增加而下降,特别是在接受苯妥英的患者中。对于没有接受苯妥英的肾功能受损患者,标准的12小时剂量通常是足够的。相比之下,亚治疗暴露在肾功能保留或增强的患者中更为常见,特别是当苯妥英联合给药时。这些发现支持在这些亚组中使用更高或更频繁的剂量。最后的模型提供了个体化LEV给药的框架。需要前瞻性研究来验证这些发现并指导其在临床实践中的实施。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Population Pharmacokinetics and Dose Simulation of Levetiracetam in Patients with Epilepsy: Influence of Renal Function and Phenytoin Co-Administration.

Levetiracetam (LEV) exhibits considerable interindividual pharmacokinetic variability; however, data in Thai populations remain limited. This study aimed to develop a population pharmacokinetic model of LEV, identify covariates affecting clearance, and inform individualized dosing strategies. A total of 374 LEV plasma concentrations from 264 Thai patients with epilepsy were analyzed using nonlinear mixed-effects modeling. The median age was 65.3 years (range 18.09-97.71). LEV pharmacokinetics was characterized by a one-compartment model with first-order elimination and proportional residual variability. The typical apparent clearance and volume of distribution were estimated at 2.61 L/h and 56.3 L, respectively. Clearance was significantly influenced by creatinine clearance (CrCL), estimated using the Cockcroft-Gault equation with adjusted body weight, and by phenytoin co-administration. Phenytoin increased clearance by 43.1%, while reduced CrCL was associated with lower clearance. Monte Carlo simulations demonstrated that both trough concentrations and the probability of achieving therapeutic targets (12-46 mg/L) declined with increasing CrCL, especially in patients receiving phenytoin. Standard 12-h dosing was generally sufficient for patients with impaired renal function who were not receiving phenytoin. In contrast, subtherapeutic exposure was more frequent in those with preserved or augmented renal function, particularly when phenytoin was co-administered. These findings support the use of higher or more frequent dosing in these subgroups. The final model provides a framework for individualized LEV dosing. Prospective studies are needed to validate these findings and guide their implementation in clinical practice.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Clinical Pharmacology
Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-
自引率
3.40%
发文量
0
期刊介绍: The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信