Epilepsy is a common neurologic disease that requires treatment with one or more medications. Due to the polypharmaceutical treatments, potential side effects, and drug-drug interactions associated with these medications, therapeutic drug monitoring is important. Therapeutic drug monitoring is typically performed in blood due to established clinical ranges. While blood provides the benefit of determining clinical ranges, urine requires a less invasive collection method, which is attractive for medication monitoring. As urine does not typically have established clinical ranges, it has not become a preferred specimen for monitoring medication adherence. Thus, large urine clinical data sets are rarely published, making method development that addresses reasonable concentration ranges difficult. An initial method developed and validated in-house utilized a universal analytical range of 50–5,000 ng/mL for all antiepileptic drugs and metabolites of interest in this work, namely carbamazepine, carbamazepine-10,11-epoxide, eslicarbazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, 4-hydroxyphenytoin, and topiramate. This upper limit of the analytical range was too low leading to a repeat rate of 11.59% due to concentrations >5,000 ng/mL. Therefore, a new, fast liquid chromatography–tandem mass spectrometry (LC–MS-MS) method with a run time under 4 minutes was developed and validated for the simultaneous quantification of the previously mentioned nine antiepileptic drugs and their metabolites. Urine samples were prepared by solid-phase extraction and analyzed using a Phenomenex Phenyl-Hexyl column with an Agilent 6460 LC–MS-MS instrument system. During method development and validation, the analytical range was optimized for each drug to reduce repeat analysis due to concentrations above the linear range and for carryover. This reduced the average daily repeat rate for antiepileptic testing from 11.59% to 4.82%. After validation, this method was used to test and analyze patient specimens over the course of approximately one year. The resulting concentration data were curated to eliminate specimens that could indicate an individual was noncompliant with their therapy (i.e., positive for illicit drugs) and yielded between 20 and 1,700 concentration points from the patient specimens, depending on the analyte. The resulting raw quantitative urine data set is presented as preliminary reference ranges to assist with interpreting urine drug concentrations for the nine aforementioned antiepileptic medications and metabolites.

中文翻译：

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快速尿液中抗癫痫药定量的LC-MS-MS方法。

癫痫病是一种常见的神经系统疾病，需要用一种或多种药物治疗。由于多药物治疗，潜在的副作用以及与这些药物相关的药物相互作用，治疗药物监测非常重要。由于建立的临床范围，通常在血液中进行治疗药物监测。血液提供了确定临床范围的好处，而尿液则需要一种侵入性较小的采集方法，这对于药物监测具有吸引力。由于尿液通常没有确定的临床范围，因此它尚未成为监测药物依从性的首选标本。因此，很少公开大型尿液临床数据集，从而难以开发解决合理浓度范围的方法。内部开发和验证的初始方法使用的通用分析范围为该工作中所有感兴趣的抗癫痫药物和代谢物为50–5,000 ng / mL，即卡马西平，卡马西平-10,11-环氧化物，依斯卡西平，拉莫三嗪，左乙拉西坦，奥卡西平，苯妥英，4-羟基苯妥英和托吡酯。分析范围的上限太低，由于浓度> 5,000 ng / mL，导致重复率达到11.59％。因此，开发了一种新的快速液相色谱-串联质谱（LC-MS-MS）方法，其运行时间在4分钟以内，并且可以同时定量上述9种抗癫痫药及其代谢产物。通过固相萃取制备尿液样品，并使用Phenomenex苯基-己基柱和Agilent 6460 LC-MS-MS仪器系统进行分析。在方法开发和验证过程中，针对每种药物优化了分析范围，以减少由于浓度超出线性范围和残留而导致的重复分析。这将抗癫痫药测试的平均每日重复率从11.59％降低到4.82％。验证后，此方法用于在大约一年的过程中测试和分析患者标本。对所得的浓度数据进行了整理，以消除可能表明某人不符合其治疗要求的标本（即，对非法药物呈阳性），并根据分析物从患者标本中得出20至1,700个浓度点。