Effects of age, gender and race on antiepileptic drugs

项目I的目标是确定影响老年人抗癫痫药物(AED)药代动力学和反应的临床重要因素，并开发可用于针对个人量身定制治疗的方法。医学上的标准做法是“一剂适合空气”的药物治疗方法。这种方法会增加不良反应的发生率，并降低需要个体化治疗的老人等患者的治疗效果。 抗癫痫药通常是老年患者的处方，但与不良事件和药物相互作用的发生率不成比例地相关。新的证据表明，高龄、性别、种族和基因均显著影响AED的药代动力学和治疗反应。这项拟议的研究建立在当前项目(1997-2002)的基础上，将确定卡马西平(CBZ)的代谢是否主要由细胞色素P450(CYP)介导。 同工酶3A4/5在老年人、妇女和非裔美国人中发生改变。还将启动托吡酯(TPM)的初步研究，以确定其药代动力学是否随着年龄的增长而变化。托吡酯是一种基本上由CYP酶代谢的新型AED。具有不同患者人口统计的三个癫痫中心将参与该项目，以确保有足够的受试者池。一种新的稳定标记(非放射性)CBZ的静脉制剂已经被 在本项目期间制定，并将对TPM采用类似的办法。静脉注射同位素是在稳态条件下严格描述药代动力学的唯一有效方法，CBZ或TPM同位素将作为患者日常剂量的一部分给予患者。已标记药物和未标记药物的CBZ或TPM及其代谢物将用液体或气相色谱-质谱法进行测定。卡马西平 将在40名65岁的老年患者和50名18-50岁的高加索人和50名非裔美国人的男女中进行药代动力学研究。受试者还将接受CYP3A5*1多态的基因分型，该多态可能显著增加CBZ的代谢，特别是在非裔美国人中。药代动力学和基因分型结果将 比较老年人和年轻人、男人和女人、非洲裔美国人和高加索人。在停用CBZ后，将对老年和成年患者的亚组进行重新研究，以衡量年龄对酶诱导的速度和程度的影响。本研究将在12名老年患者和12名成人患者身上研究增龄对TPM药代动力学和代谢的影响。这项建议的独特方面包括首次在人体内使用静脉注射CBZ和TPM配方，调查CBZ止痛药与性别、种族和/或基因的关系，以及使用TPM稳定标记的同位素进行人体药代动力学研究。项目1、2、3和4的综合结果将提供临床医生可用于个体化药物治疗的信息，支持在老年人和其他人群中进行对照试验的设计，并将作为专业人员的证据 组织可以使用关于老年人使用AEDs的发展建议。

The goal of Project I is to identify clinically significant factors that affect antiepileptic drug (AED) pharmacokinetics and response in the eldedy and to develop methods that can be used to tailor therapy to the individual. The standard practice in medicine is a "one dose fits air' approach to drug therapy. This approach results in an increased incidence of adverse effects and diminished therapeutic effect for patients such as the eldedy who require individualized therapy. AEDs are commonly prescribed for elderly patients, but are associated with a disproportionately high rate of adverse events and drug interactions. Emerging evidence indicates that advanced age, gender, race, and genotype each significantly affect AED pharmacokinetics and therapeutic response. The proposed studies, which build on the current project (1997-2002), will determine if carbamazepine (CBZ) metabolism, primarily mediated by cytochrome P450 (CYP) isoenzymes 3A4/5 is altered in the elderly, women and African Americans. Preliminary studies will also be initiated with topiramate (TPM), a newer AED substantially metabolized by CYP enzymes, to determine if its pharmacokinetics change with advancing age. Three epilepsy centers with diverse patient demographics will participate in the project to ensure an adequate subject pool. A novel intravenous formulation of stable-labeled (non-radioactive) CBZ has been developed during the present project and a similar approach will be used for TPM. Use of intravenously administered isotopes is the only available method to rigorously characterized pharmacokinetics under steady-state conditions The CBZ or TPM isotope will be administered to patients as part of their daily dose. CBZ or TPM and their metabolites from labeled and unlabeled drug will be measured by liquid or gas chromatography-mass spectrometry. Carbamazepine pharmacokinetics will be characterized in 40 elderly (->65 yrs) patients and 50 Caucasian and 50 African-American men and women age18-50 yrs. Subjects will also be genotyped for the presence of a CYP3A5*1 polymorphism that may significantly increase CBZ metabolism, particularly in African Americans. The pharmacokinetic and genotype results will be compared between elderly and younger adults, men and women, and Afdcan Americans and Caucasians. A subgroup of eldedy and adult patients will be re-studied following CBZ discontinuation to measure the effect of age on the rate and extent of enzyme induction. The effect of advancing age on TPM pharmacokinetics and metabolism will be studied in 12 elderly and 12 adult patients. Unique aspects of this proposal include the first ever use of an intravenous CBZ and TPM formulations in humans, investigation of the relationship of CBZ pharrnacoldnetics and gender, race and/or genotype, and use of a TPM stable-labeled isotope for human pharmacokinetic studies. The combined results from Projects 1,2, 3, and 4 will provide information that clinicians can use to individualize drug therapy, supports the design of controlled trials in the elderly and other populations, and will serve as evidence that professional organizations can use for the development recommendations on the use of AEDs in the eldedy.