伏立康唑在肝移植术后感染患者中的治疗药物监测  

Therapeutic drug monitoring of Voriconazole in liver transplant patients

作　　者：刘俊兰 宋燕[1] 张洁[1] 李敏[1] Liu Junlan;Song Yan;Zhang Jie;Li Min(Department of Laboratory Medicine,Renji Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 200127,China)

机构地区：[1]上海交通大学医学院附属仁济医院检验科,上海200127

出　　处：《中华检验医学杂志》2025年第3期346-351,共6页Chinese Journal of Laboratory Medicine

基　　金：国家自然科学基金(82402734);上海市“科技创新行动计划”自然科学基金(24ZR1445000);上海市公共卫生研究专项(2024GKQ35)。

摘　　要：目的观察伏立康唑血药浓度监测在肝移植受者个体化给药方面的临床应用,评估血药浓度与疗效和安全性的关系。方法回顾性病例对照研究,收集2019年8月2日至2023年5月28日期间于上海交通大学医学院附属仁济医院进行肝移植手术的受者55例,其中男性33例,女性22例;年龄(41.94±22.12)岁。所有患者均使用过伏立康唑,共计接受了235次伏立康唑血药浓度检测。采用液相色谱串联质谱法检测伏立康唑血药浓度,比较不同药物浓度水平与疗效(真菌培养与鉴定结果转阴)和肝毒性(ALT、AST和ALP均高于正常区间上限的3倍以上)的相关性,采用多元线性回归分析伏立康唑血药浓度的影响因素。结果个体间和个体内的伏立康唑血药浓度的变异系数(CV)分别为94%和58%。球蛋白水平在3种不同血药浓度(<1μg/ml,1~5.5μg/ml,>5.5μg/ml)组间的差异有统计学意义(H=8.65,P=0.013)。受试者工作特征曲线分析显示谷浓度<1.0μg/ml时治疗失败的风险增加,曲线下面积(AUC)为0.75;谷浓度>4.4μg/ml时肝毒性的风险增加(AUC=0.62)。多元线性回归分析显示质子泵抑制剂(|t|=8.07,P<0.001)和其他抗真菌药物(|t|=3.82,P<0.001)的合并用药与伏立康唑血药浓度呈显著正相关,糖皮质激素(|t|=5.60,P<0.001)和抗病毒药物(|t|=3.59,P<0.001)的使用与伏立康唑血药浓度呈显著负相关。结论肝移植受者的伏立康唑血药浓度个体间差异大,受到给药方式和合并用药种类等因素的影响。控制血药浓度在在1.0~4.4μg/ml范围内能在优化疗效的同时减少毒副反应发生。Objective To assess the clinical application of voriconazole therapeutic drug monitoring in the individualized dosing of liver transplant recipients,aiming to optimize its therapeutic efficacy and safety.Methods This is a single-center,case-control study that collected data from 55 liver transplant recipients at Renji Hospital,Shanghai Jiao Tong University School of Medicine,between August 2,2019,and May 28,2023.Among the participants,33 were male and 22 were female,with an average age of(41.94±22.12)years.All patients received voriconazole,with a total of 235 drug concentration tests conducted.The concentrations of voriconazole were measured by liquid chromatography-tandem mass spectrometry.The study analyzed the correlation between different drug concentration levels and efficacy outcomes(negative fungal culturing result)and hepatoxicity(ALT,AST,and ALP exceeding three times the upper limit of normal).Factors influencing voriconazole concen tration levels were assessed using multiple linear regression analysis.Results The coefficient of variation(CV)for inter-individuals and intra-individuals voriconazole blood concentration was 94%and 58%,respectively.The difference in globulin levels among three groups with different drug concentrations(<1μg/ml,1-5.5μg/ml,>5.5μg/ml)was statistically significant(H=8.65,P=0.013).Receiver operating characteristic curve analysis indicated that the risk of treatment failure increased when the trough concentration was<1.0μg/ml,with an area under the curve(AUC)of 0.75;the risk of hepatotoxicity increased when the drug concentration was>4.4μg/ml(AUC=0.62).Multiple linear regression analysis showed that the combined use of proton pump inhibitors(|t|=8.07,P<0.001)and other antifungal agents(|t|=3.82,P<0.001)was significantly positively correlated with voriconazole concentration,while the use of glucocorticoids(|t|=5.60,P<0.001)and antiviral drugs(|t|=3.59,P<0.001)was significantly negatively correlated with voriconazole concentration.Conclusion There is significant inter-individu

关 键 词：真菌病 侵袭性真菌病 伏立康唑 肝移植 治疗药物监测 串联质谱法 

分 类 号：R657.3[医药卫生—外科学]