Real-world interpatient variability in the pharmacokinetics of levetiracetam

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2025-02-05 DOI:10.1111/fcp.13059

Alina Chykharivska, Leonid Kagan, Mary Wagner, Luigi Brunetti

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Abstract

Background

Levetiracetam (LEV) is an antiepileptic drug (AED) used to treat a variety of seizures in adult and pediatric populations. It is an ideal AED due to its favorable pharmacokinetic (PK) and pharmacodynamic profile and lack of interactions with other AEDs.

Methods

This retrospective cohort study was designed to identify covariates that affect LEV clearance and volume of distribution and to generate a population PK model. Adults with a seizure history receiving LEV during hospital admission with a minimum of one serum LEV concentration available were included in the study. Population PK modeling and covariate testing was performed with MONOLIX Suite 2020R1 (Lixoft, France).

Results

A total of 162 serum concentrations were collected from 143 patients. Age, sex, body weight descriptors, serum creatinine, creatinine clearance (CrCL), serum albumin, liver enzymes, and total bilirubin were evaluated. Body surface area (BSA) was a significant covariate for the apparent volume of distribution (V/F). The exclusion of BSA as a covariate of V/F increased the objective function value (OFV) 5.6. CrCL was a significant covariate of apparent plasma clearance (CL/F). The exclusion of CrCL increased the OFV by 18.16 and significantly increased the root square error (RSE) % of the between-subject variabilities of the parameters.

Conclusion

LEV clearance is an effective predictor of serum concentration. CrCL was a significant covariate influencing LEV clearance, and BSA was found to influence the volume of distribution. Further studies are needed to determine the effect of body weight descriptors on LEV clearance and, ultimately, outcomes.

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真实世界中左乙拉西坦药代动力学的患者间变异性

背景左乙拉西坦（LEV）是一种抗癫痫药物（AED），用于治疗成人和儿童人群的各种癫痫发作。由于其良好的药代动力学（PK）和药效学特征以及与其他AED缺乏相互作用，它是一种理想的AED。方法本回顾性队列研究旨在确定影响LEV清除率和分布体积的协变量，并建立种群PK模型。在住院期间有癫痫发作史且至少有一种血清LEV浓度可用的成人纳入研究。使用MONOLIX Suite 2020R1 （Lixoft, France）进行种群PK建模和协变量检验。结果143例患者共采集162项血清浓度。评估年龄、性别、体重描述符、血清肌酐、肌酐清除率（CrCL）、血清白蛋白、肝酶和总胆红素。体表面积（BSA）是表观分布体积（V/F）的显著协变量。排除BSA作为V/F的协变量增加了目标函数值（OFV） 5.6。CrCL是表观血浆清除率（CL/F）的显著协变量。排除CrCL后，OFV增加了18.16%，参数的受试者间变异的根方误差（RSE） %显著增加。结论LEV清除率是血药浓度的有效预测因子。CrCL是影响LEV清除率的显著协变量，BSA影响分布体积。需要进一步的研究来确定体重描述符对LEV清除率和最终结果的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.