LC-MS/MS 法测定干血斑中卡马西平、拉莫三嗪和左乙拉西坦的分析和临床验证。

Analytical and clinical validation of an LC-MS/MS method for carbamazepine, lamotrigine and levetiracetam in dried blood spots.

机构信息

Clinical Pharmacy, Isala, Zwolle, The Netherlands

SEIN, Zwolle, The Netherlands.

出版信息

Eur J Hosp Pharm. 2024 Aug 22;31(5):450-454. doi: 10.1136/ejhpharm-2022-003589.

DOI:10.1136/ejhpharm-2022-003589

PMID:36894298

Abstract

OBJECTIVES

Therapeutic drug monitoring is performed routinely in patients on anti-epileptic drugs (AEDs) for optimisation and individualisation of therapy. The dried blood spot (DBS) sampling technique is a suitable, more patient-friendly alternative for conventional venous sampling methods. However, before DBS can be used in routine care, data are needed to establish the correlation between standard plasma concentrations obtained from venous puncture and concentrations measured through DBS obtained by finger prick. This study aims to investigate the correlation between carbamazepine, lamotrigine and levetiracetam drug concentrations in venous blood and DBS samples in the same patients at the same time.

METHODS

Clinical validation was conducted by direct comparison of paired DBS and venous plasma samples. Method agreement was evaluated using Passing-Bablok regression analysis and Bland-Altman plots to provide insight into the relationship between the two analytically validated methods. For Bland-Altman analysis the acceptance limit required by both FDA and EMA guidelines is at least two-thirds (67%) of the paired samples within 80-120% of the mean of both methods.

RESULTS

Paired samples from 79 patients were studied. For all three AEDs, plasma and DBS concentrations correlated highly (r=0.90 for carbamazepine, r=0.93 for lamotrigine and r=0.93 for levetiracetam), indicating a linear relationship. For carbamazepine and lamotrigine, no proportional or constant bias was revealed. For levetiracetam, concentrations were higher in plasma samples than in DBS (slope 1.21), implying a conversion factor is needed. The acceptance limit was met for carbamazepine and levetiracetam with a value of 72% and 81%, respectively. For lamotrigine, this acceptance limit was not met with a value of 60%.

CONCLUSIONS

The method was successfully validated and will be used for therapeutic drug monitoring in patients using carbamazepine, lamotrigine and/or levetiracetam.

摘要

目的

治疗药物监测在接受抗癫痫药物（AEDs）治疗的患者中常规进行，以优化和个体化治疗。干血斑（DBS）采样技术是一种更适合患者的替代传统静脉采样方法。然而，在 DBS 可用于常规护理之前，需要数据来建立从静脉穿刺获得的标准血浆浓度与通过手指刺破获得的 DBS 测量的浓度之间的相关性。本研究旨在调查同一患者同一时间静脉血和 DBS 样本中卡马西平、拉莫三嗪和左乙拉西坦药物浓度之间的相关性。

方法

通过直接比较配对的 DBS 和静脉血浆样本进行临床验证。使用 Passing-Bablok 回归分析和 Bland-Altman 图评估方法一致性，以深入了解两种经分析验证的方法之间的关系。对于 Bland-Altman 分析，FDA 和 EMA 指南要求的接受限值至少为两种方法平均值的 80-120%范围内的配对样本的三分之二（67%）。

结果

研究了 79 名患者的配对样本。对于所有三种 AED，血浆和 DBS 浓度高度相关（卡马西平 r=0.90，拉莫三嗪 r=0.93，左乙拉西坦 r=0.93），表明存在线性关系。对于卡马西平和平拉莫三嗪，未发现比例或常数偏差。对于左乙拉西坦，血浆样本中的浓度高于 DBS（斜率 1.21），这意味着需要转换因子。卡马西平和左乙拉西坦的接受限值分别为 72%和 81%，符合要求。对于拉莫三嗪，该接受限值为 60%，不符合要求。