Therapeutic Drug Monitoring of Antiepileptic Drugs

Therapeutic Drug Monitoring of Antiepileptic Drugs

Special report from Sheng Feng, Ph.D., Assistant Professor at Baylor College of Medicine, Baylor St. Luke’s Medical Center. Houston, TX and Nguyen Nguyen, Ph.D., Clinical Chemist & Safety Officer at Baylor Scott and White Medical Center – Temple, TX

Editors: Zhicheng Jin, PhD, DABCC, Assistant Professor, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI; Yu Jada Zhang, MD, PhD, DABCC, NRCC, Associate Director of Clinical Chemistry and POCT, UMass Memorial Health Care, Worcester, MA.

Epilepsy affects >3.4 million adults and children in the USA, 10 million in China, and >65 million globally. Antiepileptic drugs (AEDs) have been broadly used in monotherapy or combination therapy for years, while their pharmacokinetics remains variable among patients. Adverse side effects of AEDs include cognitive impairment, endocrine dysfunction, teratogenic effects, and toxicity, among others. There are 27 AEDs licensed for clinical use (1). It has been noted that some AEDs, including carbamazepine, oxcarbazepine, lacosamide, pregabalin, and eslicarbazepine, have a high potential for abuse. Because of narrow therapeutic index, potential protein binding, drug-drug pharmacokinetic interaction, or inter-individual variability, therapeutic drug monitoring (TDM) is commonly performed to optimize seizure management with minimum adverse drug effects and to assess patient compliance.

Testing methods used for AEDs include liquid chromatography (LC) coupled with ultraviolet (UV) or evaporative light scattering (LS) detectors and fluorescence polarization or enzyme-multiplied immunoassays. Recently, liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been implemented to improve analytical sensitivity and specificity (2-4). The MS/MS has higher implementation and usage complexity compared to the other platforms, but it provides the flexibility to monitor new drugs that may become available in the future. In addition, the MS/MS can be used for other applications such as drug monitoring relevant to pain management, toxicology, forensics, and biomarker analysis.

Other potential improvements to AED monitoring include moving away from standard serum or plasmasamples and increasing the use of urine and saliva samples, which are less invasive for patients (5). However, this would require the development of standardized collection processes and well-defined reference ranges suitable for a particular patient population.

The key to successful clinical outcomes, including avoiding substance abuse and adverse effects as well as optimal seizure control, remains centered on the physician-patient relationship with a reinforcing structure involving nurses and pharmacists. AED monitoring may be a useful tool supporting that relationship and informed decision making within it.

抗癫痫药的治疗药物检测

癫痫是最常见的神经系统疾病之一。在美国,超过 340 万成人和儿童承受癫痫的困扰,在中国这一数字是约1000 万,而在全球超过 6500 万人承受癫痫的折磨。多年来,抗癫痫药物被单独使用作为单一疗法或组合使用作为联合疗法来治疗这种病痛,但是这些药物的代谢动力学在不同的病人中有着很大的差异。抗癫痫药物的不良副作用包括认知障碍、内分泌功能紊乱、妊娠期间的致畸作用、还有毒性反应等。现已有27种药物批准用于治疗癫痫(1)。值得注意的是一些抗癫痫药物例如卡马西平、奥卡西平、拉考沙胺、普瑞巴林和艾司利卡西平都有一定的滥用倾向。由于部分药物治疗指数低,可能与蛋白质结合,药代动力学间相互影响,以及个体差异,治疗药物监测通常用于帮助医生优化癫痫控制,减低不良药物反应,以及评估病人是否遵医嘱用药。

目前有多种分析检验方法已用于检测抗癫痫药物。这些方法包括液相色谱串联紫外检测 (LC-UV) 、液相色谱与蒸发光散射检测、荧光偏振免疫测定、和酶倍增免疫测定。最近基于液相色谱串联质谱的检验方法可提供更高的选择性和灵敏度 (2-4)。与其他检验方法相比,串联质谱在使用上更加的复杂,但是串联质谱可以灵活地适应未来出现的新药物的检测。此外,串联质谱技术也有其他的广泛应用,比如止痛药物检测、毒理学检验、法医检验、生物标志物分析。

抗癫痫药物检测可以通过改变检测基质进一步改进。相较于目前的血清和血浆检测,尿液和唾液在采集时侵入性更小,是更理想的检验对象(5)。然而使用尿液和唾液代替血浆作为抗癫痫药物检测需要进一步的完善,例如标准化采集步骤和为不同的族群建立明确的药物浓度范围。

治疗成功的关键包括避免药物滥用和不良药物反应以及优化癫痫控制效果。达成这些目标的核心是有效的医生病人的配合,护士和药剂师的参与进一步强化这种配合关系。抗癫痫药物检测是支持这种关系并为其中的决策提供信息的有效工具。

References

1. Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: A 2018 update. Ther Drug Monit. 2018; 40:526-548.

2. Kim KB, Seo KA, Kim SE, Bae SK, Kim DH, Shin JG. Simple and accurate quantitative analysis of ten antiepileptic drugs in human plasma by liquid chromatography/tandem mass spectrometry. J Pharm Biomed Anal. 2011;56(4):771-777. doi:10.1016/j.jpba.2011.07.019

3. Shibata M, Hashi S, Nakanishi H, Masuda S, Katsura T, Yano I. Detection of 22 antiepileptic drugs by ultra-performance liquid chromatography coupled with tandem mass spectrometry applicable to routine therapeutic drug monitoring. Biomed Chromatogr. 2012;26(12):1519-1528. doi:10.1002/bmc.2726

4. Feng S., Bridgewater B., Strickland E.C., McIntire G.; A rapid LC–MS–MS method for the quantitation of antiepileptic drugs in urine. J. Anal. Toxicol. 44(7), 688–696 (2020).

5. Patrick M, Parmiter S, Mahmoud S.H.; Feasibility of Using Oral Fluid for

Therapeutic Drug Monitoring of Antiepileptic Drugs, Eur. J. Drug Metab.

Pharmacokinet. 46 (2) (2021) 205–223.

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