Epilepsy Clinical Research Program

描述(申请人提供)：癫痫的发病率在60岁以后迅速上升，75岁以上的报告发病率为1.48%。在当前P50期间进行的药物流行病学研究表明，社区老年人中抗癫痫药物(AED)的使用率约为2%(医疗保健财务管理局数据集(n=~12,000/年))，疗养院居民(贝弗利数据集)约为9%。显然，在不久的将来，使用AEDs的老年人的绝对数量将大幅增加，但人们对这些强大的神经功能调节剂在这一人群中的安全和有效使用知之甚少。这个为期5年的计划项目的目标是增加我们对AEDs在老年人中的药代动力学(PK)、药效学(PD)和药物流行病学(PE)的了解。这些信息对于设计适当的对照试验和为这一人群制定循证指南至关重要。我们将使用多种方法来研究这些问题，包括体外肝脏中的肝微粒体、志愿者中的稳定标记同位素、非线性混合效应建模(Nome)以及将估计的AED浓度应用于大量疗养院人群的结果。将进行广泛的CYP3A4/5基因分型，并对AED代谢的遗传和种族因素进行初步调查。卡马西平(CBZ)、丙戊酸(VPA)、拉莫三嗪(LTG)和托吡酯(TPM)在老年患者中的PK特征将用本课题组开发的稳定的标记静脉制剂进行测定。NONMEM分析将使用来自明尼苏达州、亚特兰大、迈阿密和国家退伍军人管理局合作研究的临床数据进行。这三个网站将提供有史以来研究过的最大规模的老年癫痫患者群体，并有足够的能力检验这些假设。关于苯妥英钠(PHT)、CBZ和VPA PK的研究结果将应用于现有的贝弗利疗养院数据库中的剂量、体重和结果测量。这将使我们能够估计该人群中的AED浓度，并确定与高、中或低浓度相关的不良事件的患病率和类型。从这项多管齐下的工作中获得的信息将对老年人使用AEDs产生深远的影响。

DESCRIPTION (provided by applicant): The incidence of epilepsy rises rapidly after age 60 with a reported prevalence of 1.48% for persons over 75. Pharmacoepidemiologic studies performed during the current P50 show that the prevalence of anti epileptic drug (AED) use is approximately 2% among the community-dwelling elderly (Health Care Finance Administration data set (n = ~12,000/yr) and approximately 9% among nursing home residents (Beverly data set). Clearly, the absolute number of elderly using AEDs will increase greatly in the near future, but very little is known about the safe and effective use of these powerful modulators of neurological functioning in this population. The goal of this 5-year program project is to increase our knowledge of the pharmacokinetics (PK), pharmacodynamics (PD), and pharmacoepidemiology (PE) of AEDs in the elderly. This information is critical for the design of appropriate controlled trials and the development of evidence-based guidelines for this population. We will investigate these issues using a variety of approaches including hepatic microsomes in vitro liver, stable labeled isotopes in volunteers, non-linear mixed effect modeling (NOME) and application of estimated AED concentrations to outcomes in a large nursing home population. Extensive genotyping of CYP3A4/5 and initial investigation of genetic and racial factors in AED metabolism will be carried out. The PK characteristics of carbamazepine (CBZ), valproic acid (VPA), lamotrigine (LTG), and topiramate (TPM) in elderly patients will be determined using stable labeled intravenous preparations developed by our group. NONMEM analysis will be performed using clinical data from Minnesota, Atlanta, Miami, and the national Veterans Administration Cooperative Study. These 3 sites will provide the largest group of elderly persons with epilepsy ever studied and have enough power to test the hypotheses. Findings regarding phenytoin (PHT), CBZ and VPA PK from the current and proposed P50 will be applied to dose, weight, and to outcome measures in the extant Beverly Nursing Home database. This will allow us to estimate AED concentrations in this population and determine prevalence and type of adverse events associated with high, middle, or low concentrations. The information obtained from this multi-pronged effort will have profound impact on the use of AEDs in the elderly.