Effects of age, gender and race on antiepileptic drugs

年龄、性别和种族对抗癫痫药物的影响

• 批准号: 7119178
• 负责人: JAMES C. CLOYD
• 金额: $ 33.45万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119178
• 关键词: African American; age difference; anticonvulsants; blood chemistry; carbamazepine; caucasian American; cytochrome P450; drug metabolism; enzyme activity; enzyme induction /repression; epilepsy; gas chromatography mass spectrometry; gender difference; genetic polymorphism; human old age (65+); human subject; intravenous administration; patient oriented research; pharmacokinetics; racial /ethnic difference; stable isotope; urinalysis

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.

项目I的目的是确定临床上重要的因素，这些因素会影响埃尔迪迪邦的抗癫痫药（AED）药代动力学和反应，并开发可用于为个人调整治疗的方法。医学中的标准实践是“一剂适合空气”的药物治疗方法。这种方法导致不良反应的发生率增加，并且对需要个性化治疗的善良的患者（例如患者）的治疗作用减少。 AED通常针对老年患者开具，但与不成比例的不良事件和药物相互作用相关。新兴的证据表明，高级，性别，种族和基因型各自都会显着影响AED药代动力学和治疗反应。拟议的研究基于当前项目（1997-2002），将确定卡马西平（CBZ）代谢是否主要由细胞色素P450（CYP）介导 老年人，妇女和非裔美国人的同工酶3A4/5发生了变化。初步研究还将通过托吡酯（TPM）（TPM）进行，这是一种由CYP酶代谢的较新的AED，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的癫痫中心将参与该项目，以确保有足够的主题库。一种新型的稳定标记（非放射性）CBZ的静脉注射配方已有 在本项目中开发的，TPM将使用类似的方法。使用静脉注射的同位素是在稳态条件下进行严格表征药代动力学的唯一可用方法，CBZ或TPM同位素将作为每日剂量的一部分给患者施用。 CBZ或TPM及其来自标记和未标记药物的代谢产物将通过液态或气相色谱 - 质谱法测量。卡马西平 药代动力学将在40名老年人（ - > 65岁）和50名高加索人和50名非裔美国人男性和女性中进行表征。18-50岁。受试者还将针对存在CYP3A5*1多态性的受试者可能会显着增加CBZ代谢，尤其是在非裔美国人中。药代动力学和基因型结果将 比较老年人和年轻人，男女之间，以及AFDCAN的美国人和高加索人。 CBZ停用后，将重新研究弱体和成年患者的亚组，以衡量年龄对酶诱导率和程度的影响。在12名老年患者和12名成人患者中，将研究促进年龄对TPM药代动力学和代谢的影响。该提案的独特方面包括在人类中首次使用静脉内CBZ和TPM配方，研究CBZ Pharrnacoldnetics与性别的关系，种族和/或基因型，以及使用TPM稳定标记的同位素用于人类药物学研究。项目1,2、3和4项目的综合结果将提供临床医生可以用来个性化药物治疗的信息，支持老年人和其他人群的对照试验的设计，并将作为证据表明专业 组织可以用于用于使用EED在Eldedy中使用AED的开发建议。