Velghe Sofie, Stove Christophe P
Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.
Anal Bioanal Chem. 2018 Mar;410(9):2331-2341. doi: 10.1007/s00216-018-0866-4. Epub 2018 Jan 23.
Dosage adjustment of anti-epileptic drugs by therapeutic drug monitoring (TDM) is very useful, especially for the first-generation anti-epileptic drugs (AEDs). Microsampling-the collection of small volumes of blood-is increasingly considered a valuable alternative to conventional venous sampling for TDM. Volumetric absorptive microsampling (VAMS) allows accurate and precise collection of a fixed volume of blood, eliminating the volumetric blood hematocrit bias coupled to conventional dried blood spot collection. The aim of this study was to develop and validate an LC-MS/MS method for the determination and quantification of four anti-epileptic drugs (carbamazepine, valproic acid, phenobarbital, and phenytoin) and one active metabolite (carbamazepine-10,11-epoxide) in samples collected by VAMS. The method was fully validated based on international guidelines. Precision (%RSD) was below 10%, while, with a single exception, accuracy (%bias) met the acceptance criteria. Neither carry-over nor unacceptable interferences were observed, the method being able to distinguish between the isomers oxcarbazepine and carbamazepine-10,11-epoxide. All compounds were stable in VAMS samples for at least 1 month when stored at room temperature, 4 °C, and - 20 °C and for at least 1 week when stored at 60 °C. Internal standard-corrected matrix effects were below 10%, with %RSDs below 4%. High (> 85%) recovery values were obtained and the effect of the hematocrit on the recovery was overall limited. Successful application on external quality control materials and on left-over patient samples demonstrated the validity and applicability of the developed procedure. Graphical abstract Graphical representation of the sampling, chemical structures, and the resulting chromatogram for volumetric absorptive microsampling (VAMS)-based therapeutic drug monitoring of first-generation anti-epileptic drugs by liquid chromatography with tandem mass spectrometric detection.
通过治疗药物监测（TDM）调整抗癫痫药物的剂量非常有用，尤其是对于第一代抗癫痫药物（AEDs）。微量采样——采集少量血液——越来越被认为是用于TDM的传统静脉采样的一种有价值的替代方法。体积吸收微量采样（VAMS）能够准确精确地采集固定体积的血液，消除了与传统干血斑采集相关的体积血细胞比容偏差。本研究的目的是开发并验证一种液相色谱-串联质谱（LC-MS/MS）方法，用于测定和定量通过VAMS采集的样品中的四种抗癫痫药物（卡马西平、丙戊酸、苯巴比妥和苯妥英）以及一种活性代谢物（卡马西平-10,11-环氧化物）。该方法根据国际指南进行了全面验证。精密度（%RSD）低于10%，除了一个例外，准确度（%偏差）符合验收标准。未观察到残留或不可接受的干扰，该方法能够区分异构体奥卡西平和卡马西平-10,11-环氧化物。所有化合物在VAMS样品中于室温、4℃和-20℃储存时至少稳定1个月，在60℃储存时至少稳定1周。内标校正的基质效应低于10%，%RSD低于4%。获得了较高（>85%）的回收率值，血细胞比容对回收率的影响总体有限。在外部质量控制材料和剩余患者样品上的成功应用证明了所开发方法的有效性和适用性。图形摘要基于体积吸收微量采样（VAMS）的第一代抗癫痫药物治疗药物监测的采样、化学结构以及液相色谱-串联质谱检测所得色谱图的图形表示。
