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，并开发可用于个性化治疗的方法。医学上的标准做法是“一剂空气”的药物治疗方法。这种方法导致不良反应的发生率增加，并且对需要个体化治疗的患者（例如老年人）的治疗效果降低。 AED通常用于老年患者，但与不成比例的高不良事件和药物相互作用率相关。新出现的证据表明，高龄、性别、种族和基因型均显著影响AED的药代动力学和治疗反应。在当前项目（1997-2002）的基础上，拟议的研究将确定主要由细胞色素P450（CYP）介导的卡马西平（CBZ）代谢 同工酶3A 4/5在老年人、妇女和非裔美国人中发生改变。初步研究也将开始与托吡酯（TPM），一个较新的AED基本上代谢酶，以确定其药代动力学是否随着年龄的增长而变化。三个具有不同患者人口统计学特征的癫痫中心将参与该项目，以确保有足够的受试者库。一种新的稳定标记的（非放射性）CBZ静脉制剂已被 在本项目期间开发了一个类似的方法，并将用于TPM。使用静脉内给药的同位素是在稳态条件下严格表征药代动力学的唯一可用方法。CBZ或TPM同位素将作为患者每日剂量的一部分给予患者。CBZ或TPM及其来自标记和未标记药物的代谢物将通过液相或气相色谱-质谱法进行测量。卡马西平 将在40名老年（~>65岁）患者和50名高加索人和50名非裔美国人18 -50岁的男性和女性中表征药代动力学。还将对受试者进行基因分型，以确定是否存在可能显著增加CBZ代谢的CYP 3A 5 *1多态性，特别是在非裔美国人中。药代动力学和基因型结果将 在老年人和年轻人、男性和女性、Afdcan美国人和高加索人之间进行比较。在CBZ停药后，将重新研究老年和成人患者亚组，以测量年龄对酶诱导率和程度的影响。将在12例老年患者和12例成人患者中研究年龄增长对TPM药代动力学和代谢的影响。该提案的独特之处包括首次在人体中使用静脉注射CBZ和TPM制剂，研究CBZ药效学与性别、种族和/或基因型的关系，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的综合结果将为临床医生提供个性化药物治疗的信息，支持在老年人和其他人群中设计对照试验，并将作为专业药物治疗的证据。 组织可以用于制定老年人使用AED的建议。

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.