Anderson Gail D
Department of Pharmacy, University of Washington, Seattle, Washington 98195, USA.
Ther Drug Monit. 2008 Apr;30(2):173-80. doi: 10.1097/FTD.0b013e318167d11b.
Therapeutic drug monitoring (TDM) is widely accepted as a method to improve the effectiveness and safety of the first generation antiepileptic drugs (AEDs) and to identify an individual's optimum concentration. Like the older AEDs, the new AEDs also have significant pharmacokinetic variability. A similar relationship between concentration and effect for the new and old AEDs in experimental seizure models suggests that it is reasonable to use TDM for the new AEDs. With the addition of generic formulations of the new AEDs, TDM can play an important role to validate bioequivalence in patients. There is a history of problems with generics of the older AEDs, primarily carbamazepine and phenytoin. The Biopharmaceutics Classification System, which correlates the solubility and permeability of a drug with oral drug absorption, predicts that there should be no significant problems with the majority of the new AEDs. Because of the controversy over the risk-benefit of generic substitution of AEDs, the use of TDM will provide a way to ensure patient safety while establishing that generics of AEDs proven to be bioequivalent in population studies are also bioequivalent in individuals. The goal of personalized medicine is to use genetic testing to target therapy and identify those individuals unlikely to respond to a drug or likely to respond adversely to the same drug. Of all the AEDs, only phenytoin undergoes significant metabolism by cytochrome P450 isozymes with significant genetic polymorphisms (CYP2C9, CYP2C19). Studies are still needed to identify genetic and biomarkers to identify patients at risk for serious idiosyncratic reactions. There have been significant advances in the understanding of the role of genetics in idiopathic as well as acquired epilepsies. Identification of experimental and clinical evidence linking functional changes associated with gene mutations to epilepsy syndromes will help provide new molecular targets for future AEDs.
治疗药物监测（TDM）作为一种提高第一代抗癫痫药物（AEDs）有效性和安全性以及确定个体最佳血药浓度的方法，已被广泛接受。与老一代AEDs一样，新一代AEDs也具有显著的药代动力学变异性。在实验性癫痫模型中，新一代和老一代AEDs血药浓度与效应之间存在相似关系，这表明对新一代AEDs使用TDM是合理的。随着新一代AEDs通用制剂的增加，TDM在验证患者生物等效性方面可发挥重要作用。老一代AEDs的通用制剂，主要是卡马西平和苯妥英，曾出现过问题。生物药剂学分类系统将药物的溶解度和渗透性与口服药物吸收相关联，预测大多数新一代AEDs不会有重大问题。由于AEDs通用替换的风险效益存在争议，TDM的使用将提供一种确保患者安全的方法，同时确定在群体研究中被证明生物等效的AEDs通用制剂在个体中也具有生物等效性。个性化医疗旨在通过基因检测来靶向治疗，并识别那些不太可能对某种药物产生反应或可能对同一药物产生不良反应的个体。在所有AEDs中，只有苯妥英通过具有显著基因多态性的细胞色素P450同工酶（CYP2C9、CYP2C19）进行显著代谢。仍需开展研究以确定基因和生物标志物，从而识别有严重特异反应风险的患者。在理解遗传学在特发性癫痫和获得性癫痫中的作用方面已取得重大进展。识别将与基因突变相关的功能变化与癫痫综合征联系起来的实验和临床证据，将有助于为未来的AEDs提供新的分子靶点。
