摘要
抗血液恶性肿瘤药物常具有治疗窗窄、个体差异显著及药物相互作用风险高等特点,需通过治疗药物监测(TDM)实现个体化给药。对于化疗期间因严重骨髓抑制而引发感染需联合抗真菌治疗的患者,TDM可同时优化抗肿瘤药物与抗真菌药物的血药浓度,在确保抗肿瘤疗效的同时有效控制侵袭性真菌感染风险,这一技术已成为血液系统恶性肿瘤个体化治疗的重要支撑。本研究建立了一种基于超高效液相色谱-串联质谱的分析方法,用于同时测定人血浆中抗肿瘤药物塞利尼索(selinexor, SEL)、维奈克拉(venetoclax, VEN)及抗真菌药物伏立康唑(voriconazole, VOR)、泊沙康唑(posaconazole, POSA)。色谱分离采用Kinetex®XB-C18色谱柱(50 mm×3.0mm, 2.6µm),流动相为甲醇-含0.1%甲酸的10 mmol/L乙酸铵溶液,流速0.5 mL/min,梯度洗脱,进样量2μL,分析时间为4.0 min。采用电喷雾离子源,正离子扫描,多反应监测模式进行测定。本研究对质谱参数进行了优化,并进行了方法学验证,结果表明,该方法线性关系良好,线性相关系数(r)均大于0.994,4种药物的线性范围分别为SEL 0.04~1.48μg/mL、VEN 0.15~5.50μg/mL、VOR 0.29~11.77μg/mL和POSA 0.15~6.05μg/mL;4种药物在各浓度水平的日内精密度和日间精密度相对标准偏差(RSD)≤7.1%,提取回收率均≥85.3%,方法准确度为87.4%~109.0%。采集了30例接受SEL联合VEN治疗的急性髓系白血病患者的81份临床样本进行分析,测得SEL的血药浓度为0.049~0.646μg/mL,约30%的患者在相同疗程内SEL血药峰浓度(Cmax)差异较大。本方法可为临床实践中存在药物相互作用及个体差异的血液系统恶性肿瘤患者的个体化精准治疗提供循证依据。
Drugs used to treat hematologic malignancies often exhibit narrow therapeutic windows,significant inter-individual variability,and high risks of drug-drug interactions,necessitating therapeutic drug monitoring(TDM)for individualized dosing.For patients requiring concomitant antifungal therapy due to infections arising from severe chemotherapy-induced myelosuppression,TDM can optimize plasma concentrations of both antineoplastic and antifungal agents.This concurrent optimization ensures anti-tumor efficacy while effectively mitigating the risk of invasive fungal infections,positioning TDM as a critical component of personalized management in hematologic malignancies.This study established and validated a rapid ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)method for the simultaneous quantification of the antineoplastic agents selinexor(SEL)and venetoclax(VEN),along with the antifungal agents voriconazole(VOR)and posaconazole(POSA)in human plasma.Chromatographic separation was achieved using a Kinetex^(R)XB-C18 column(50 mm×3.0 mm,2.6μm)with a mobile phase consisting of methanol and 10 mmol/L ammonium acetate containing 0.1%formic acid,delivered at a flow rate of 0.5 mL/min under gradient elution conditions.The injection volume was 2μL,and the total run time was 4.0 min.Detection employed an electrospray ionization source operating in positive ion mode with multiple reaction monitoring(MRM).Following optimization of mass spectrometric parameters,the method underwent comprehensive validation.Calibration curves demonstrated excellent linearity(r>0.994)over the ranges of 0.04-1.48μg/mL for SEL,0.15-5.50μg/mL for VEN,0.29-11.77μg/mL for VOR,and 0.15-6.05μg/mL for POSA.Intra-day and interday precisions(RSDs)were≤7.1%at all concentration levels.Extraction recoveries were≥85.3%,demonstrating efficient and consistent sample processing.Method accuracy,determined by the percentage deviation of measured concentrations from nominal values,fell within the acceptable range of 87.4%to 109.0%across all QC levels,confirming the method’s trueness.The practical utility of the validated UHPLC-MS/MS method was demonstrated through its application to clinical specimens.We collected and analyzed 81 clinical samples from 30 patients with acute myeloid leukemia treated with the combination of SEL and VEN.Measured plasma concentrations of SEL in these patients ranged from 0.049μg/mL to 0.646μg/mL.Notably,significant inter-individual variability in the peak plasma concentration(C_(max))of SEL was observed within the same treatment cycle for approximately 30%of the patient cohort.This study offers evidence-based support for personalized precision therapy in this patient population,which exhibits substantial inter-individual variability and complex drug-drug interactions in clinical practice.
作者
肖雄
李月
胡锦芳
万青
彭洪薇
XIAO Xiong;LI Yue;HU Jinfang;WAN Qing;PENG Hongwei(Department of Pharmacy,The First Affiliated Hospital of Nanchang University,Nanchang 330000,China;School of Pharmacy,Nanchang University,Nanchang 330000,China)
出处
《色谱》
北大核心
2026年第3期349-356,共8页
Chinese Journal of Chromatography
基金
国家自然科学基金(81860035)。
关键词
超高效液相色谱-串联质谱
塞利尼索
维奈克拉
三唑类抗真菌药
治疗药物监测
ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLCMS/MS)
selinexor
venetoclax
triazole antifungal agent
therapeutic drug monitoring
