The Role of Plasma Trough Concentration of Voriconazole and Voriconazole N-Oxide in Its Hepatotoxicity in Adult Patients.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-08-13 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S475706

Lin Cheng, Xi You, Xiaowen Wang, Mingjie Yu, Changsheng Jia

{"title":"The Role of Plasma Trough Concentration of Voriconazole and Voriconazole N-Oxide in Its Hepatotoxicity in Adult Patients.","authors":"Lin Cheng, Xi You, Xiaowen Wang, Mingjie Yu, Changsheng Jia","doi":"10.2147/DDDT.S475706","DOIUrl":null,"url":null,"abstract":"Objective: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients.Materials and methods: This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry.Results: In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 μg/mL, or the VCZ CN was lower than 1.7 μg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased.Conclusion: VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7000,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330242/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S475706","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Objective: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C₀) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C₀ and plasma trough concentration of VCZ N-oxide (C_N) in hepatotoxicity in adult patients.

Materials and methods: This was a prospective study. VCZ C₀ and C_N were measured using liquid chromatography-tandem mass spectrometry.

Results: In total, 601 VCZ C₀ and C_N from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C₀ was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ C_N was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C₀ was higher than 4.0 μg/mL, or the VCZ C_N was lower than 1.7 μg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased.

Conclusion: VCZ C₀ and C_N were associated with liver function-related adverse events. Measurement of VCZ C_N should be considered for VCZ therapeutic drug monitoring.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

伏立康唑和伏立康唑 N-氧化物的血浆低浓度在成人患者肝毒性中的作用

目的：肝毒性是伏立康唑（VCZ）早期停药的一个重要原因。VCZ 的血浆谷浓度（C0）在肝毒性中的作用令人困惑。VCZ N-氧化物是 VCZ 在血浆中的主要代谢产物。我们研究了 VCZ C0 和 VCZ N-氧化物（CN）的血浆谷浓度在成年患者肝毒性中的作用：这是一项前瞻性研究。采用液相色谱-串联质谱法测量 VCZ C0 和 CN：结果：共纳入 376 名成年患者的 601 份 VCZ C0 和 CN。ALP、ALT、AST、γ-GT和TBIL的1级或以上不良反应发生率分别为35.4%、21.0%、30.1%、56.2%和22.2%。与年轻成人患者相比，老年患者（≥65 岁）发生 1 级或以上 ALP 不良事件的比例更高。在多变量分析中，VCZ C0是老年患者AST和年轻成人患者TBIL发生1级或以上不良事件的危险因素，而VCZ CN是ALT、AST和TBIL发生1级或以上不良事件的危险因素。接收器操作特征曲线分析结果表明，当VCZ C0高于4.0 μg/mL或VCZ CN低于1.7 μg/mL时，AST和TBIL的1级或以上不良事件发生率增加：结论：VCZ C0和CN与肝功能相关不良事件有关。结论：VCZ C0和CN与肝功能相关不良事件有关，在VCZ治疗药物监测中应考虑测量VCZ CN。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.