基于同位素稀释-UPLC-Q-Exactive-MS的拉考沙胺在癫痫儿童血浆中的治疗药物监测  

Therapeutic Drug Monitoring of Lacosamide in Epileptic Children’s Plasma Based on Isotope Dilution-UPLC-Q-Exactive-MS Method

作　　者：武佳璇 马英华 胡世远 赵宜乐 刘康 东蕾 WU Jiaxuan;MA Yinghua;HU Shiyuan;ZHAO Yile;LIU Kang;DONG Lei(College of Pharmacy,Hebei Medical University,Shijiazhuang 050017,China;Children’s Hospital of Hebei Province,Department of Pharmacy,Shijiazhuang 050031,China;Children’s Hospital of Hebei Province,Department of Neurology,Shijiazhuang 050031,China)

机构地区：[1]河北医科大学药学院,石家庄050017 [2]河北省儿童医院药学部,石家庄050031 [3]河北省儿童医院神经内一科,石家庄050031

出　　处：《中国现代应用药学》2024年第24期3488-3497,共10页Chinese Journal of Modern Applied Pharmacy

基　　金：河北省省级科技计划项目(202230714010408);河北省政府资助医学优秀人才项目。

摘　　要：目的建立基于超高效液相色谱-四极杆/静电场轨道阱高分辨质谱技术(UPLC-Q-Exactive-MS)同时测定癫痫患儿血浆中拉考沙胺(lacosamide,LCM)和代谢物去甲拉考沙胺(O-desmethyl lacosamide,ODL)浓度的方法,分析LCM和ODL血药浓度和用药剂量、肌酐清除率(estimated glomerular filtration rate,eGFR)之间的相关性,并对用药患者进行随访和治疗药物监测。方法血浆样品经有机溶剂沉淀蛋白后以LCM-D3为内标,0.2%甲酸-水(A)和乙腈(B)为流动相,流速为0.3 mL·min^(-1)进行梯度洗脱,柱温35℃,进样量为2μL。质谱检测采用电喷雾离子源正离子模式。考察方法的专属性、定量下限、标准曲线、残留效应、准确度、精密度、提取效率、基质效应和稳定性。使用建立的方法测定临床血浆样本,并收集临床用药剂量、eGFR等相关数据,使用SPSS 26.0软件分析数据间的相关性。对患儿进行随访,记录LCM疗效和相关不良反应,结合LCM血药浓度,优化LCM用药方案。结果LCM和ODL的血药浓度在0.10~40.00μg·mL^(−1)内线性关系良好(r>0.99),定量下限均为0.1μg·mL^(−1),专属性强,提取效率、稳定性良好,批内和批间精密度PSD均≤8.65%,不受正常血浆和溶血血浆(溶血程度≤5%)基质的影响,方法学验证均符合中国药典2020年版规定。LCM口服剂量与LCM、ODL血药浓度分别呈正相关(r=0.4058,P<0.0001;r=0.3664,P<0.0001),LCM的血药浓度与ODL的血药浓度呈弱正相关(r=0.2966,P=0.0003)。LCM与ODL的血药浓度比与患儿eGFR呈负相关(r=−0.3902,P<0.0001)。应用本方法对142例用药癫痫患儿进行血药浓度测定,并完成了125例患儿的随访,记录用药疗效,对患儿的LCM用药情况、疗效、不良反应与LCM血药浓度结合分析,LCM治疗癫痫的有效率为97.6%,不良反应发生率为29.6%。结论本研究建立了同位素稀释-UPLC-Q-Exactive-MS测定LCM和ODL浓度的方法。该方法快速、简便、稳定、经济,可应用于临床LOBJECTIVE To establish a method to simultaneously determine the plasma concentration of lacosamide(LCM)and O-desmethyl lacosamide(ODL)of children with epilepsy,which based on ultra-high performance liquid chromatographyquadrupole-electrostatic field Orbitrap mass spectrometry(UPLC-Q-Exactive-MS).Using the established method to analyze the correlation among the plasma concentration of LCM and ODL,dosage,and estimated glomerular filtration rate(eGFR).Follow-up and therapeutic drug monitoring were carried out for patients who were taking LCM.METHODS The plasma samples were pretreated by protein precipitation method.LCM-D3 as the internal standard and the gradient elution was performed with 0.2%formic acid aqueous solution(A)-acetonitrile(B)as mobile phase at a flow rate of 0.3 mL·min^(-1).The column temperature was 35℃ and the injection volume was 2μL.Electrospray ion source positive ion mode was used for mass spectrometry detection.The specificity,lower limit of quantitation,standard curve,residual,accuracy,precision,extraction efficiency,matrix effect and stability of the method were investigated.Clinical plasma samples were determined using the established method,relevant data such as clinical dosage and eGFR were collected,and the correlation between data was analyzed using SPSS 26.0 software.The included patients were followed-up and the curative effect and related adverse reactions of LCM were recorded.Combined with the LCM blood concentration,the LCM medication regimen was optimized.RESULTS The plasma concentrations of LCM and ODL showed a good linearly relationship between 0.10−40.00μg·mL^(−1)(r>0.99),lower limit of quantitation was 0.1μg·mL^(−1),strong specificity,good extraction efficiency and stability,intra-and inter-batch precision RSDs≤8.65%,unaffected by normal plasma and hemolytic plasma(≤5%)matrix.The methodology verification was in accordance with the provisions of the Chinese Pharmacopoeia 2020 edition.The oral dose of LCM was respectively positively correlated with the plasma co

关 键 词：拉考沙胺 去甲拉考沙胺 超高效液相色谱-四极杆/静电场轨道阱高分辨质谱 儿童 治疗药物监测 

分 类 号：R969.1[医药卫生—药理学]