PDF(Pubmed)
Abstract：
Cenobamate (CNB) is a new anti-seizure medication (ASM) recently introduced in clinical practice after approval by the FDA and EMA for the add-on treatment of focal onset seizures in adult patients. Although its mechanism of action has not been fully understood, CNB showed promising clinical efficacy in patients treated with concomitant ASMs. The accessibility of CNB could pave a way for the treatment of refractory or drug-resistant epilepsies, which still affect at least one-third of the patients under pharmacological treatment. In this context, therapeutic drug monitoring (TDM) offers a massive opportunity for better management of epileptic patients, especially those undergoing combined therapy. Here, we describe the first fully validated ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the quantification of CNB and concomitant ASMs in human plasma, with samples extracted either manually or by means of a liquid handler. Our method was validated according to the most recent ICH International Guideline M10 for Bioanalytical Method Validation and Study Sample Analysis. The method proved to be selective for CNB and displayed a linear range from 0.8 to 80 mg/L; no matrix effect was found (98.2 ± 4.1%), while intra-day and inter-day accuracy and precision were within the acceptance range. Also, CNB short- and long-term stability in plasma under different conditions was assessed. Leftover human plasma samples were employed as study samples for method validation. Our method proved to be highly sensitive and selective to quantify CNB and concomitant ASMs in human plasma; therefore, this method can be employed for a routinely TDM-based approach to support physicians in the management of an epileptic patient.
摘要：
Cenobamate（CNB）是一种新的抗癫痫药物（ASM），在获得FDA和EMA批准后，最近在临床实践中推出，用于成人患者局灶性发作性癫痫发作的附加治疗。虽然其作用机制尚未完全了解,CNB在伴随ASM治疗的患者中显示出有希望的临床疗效。CNB的可及性可以为难治性或耐药性癫痫的治疗铺平道路。这仍然影响至少三分之一接受药物治疗的患者。在这种情况下，治疗药物监测（TDM）为更好地管理癫痫患者提供了巨大的机会，尤其是那些接受联合治疗的人。这里,我们描述了第一个完全验证的超高效液相色谱-串联质谱（UHPLC-MS/MS）方法，用于定量人血浆中的CNB和伴随的ASM，手动或通过液体处理器提取的样品。我们的方法根据最新的ICH国际生物分析方法验证和研究样品分析指南M10进行验证。该方法对CNB具有选择性，线性范围为0.8至80mg/L；未发现基质效应（98.2±4.1％），而日间和日间准确度和精密度均在接受范围内。此外，评估CNB在不同条件下在血浆中的短期和长期稳定性。将剩余的人血浆样品用作用于方法验证的研究样品。我们的方法被证明对定量人血浆中的CNB和伴随的ASM具有高度的敏感性和选择性；因此，该方法可用于常规的基于TDM的方法,以支持医师治疗癫痫患者.
