Forecasting Topiramate's Effect on Cognitive Function

预测托吡酯对认知功能的影响

基本信息

批准号：
7490763
负责人：
SUSAN E MARINO
金额：
$ 1.09万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-11 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7490763
关键词：
age difference anticonvulsants clearance rate clinical research cognition disorders disease /disorder proneness /risk disease /therapy duration drug adverse effect drug metabolism genotype human subject intravenous administration neuropsychological tests neuropsychology pharmacogenetics pharmacokinetics psychopharmacology

项目摘要

DESCRIPTION (provided by applicant): Cognitive impairment is one of the most prevalent side effects associated with antiepileptic drugs and is a common reason for discontinuation of therapy, especially in the elderly. Due to individual variability in pharmacokinetics and sensitivity to adverse effects, it is difficult to predict which patients are at risk for developing a drug-induced deterioration in neuropsychological function. The goal of this project is to characterize the relationship among topiramate (TPM) pharmacokinetics, pharmacogenomics and cognitive functioning in order to forecast which patients are most likely to manifest significant cognitive deficits when placed on a regime that includes TPM. The effect of age and genotype on TPM pharmacokinetics will be determined using a novel, stable-labeled (non-radioactive) intravenous TPM formulation and the utility of a single point plasma concentration method to predict subsequent systemic drug exposure in an individual will be assessed. Cognitive function will be determined as an effect of age and duration of TPM therapy. Pharmacokinetic and neuropsychological measures will be correlated in order to identify factors that can be used to forecast risk for TPM induced cognitive impairment. This approach will not only aid in optimizing TPM therapy but may be applied to other AEDs and more broadly to other neuroactive medications. If successful, it will alter the common contemporary practice of pushing drugs to maximum tolerated doses.

描述（由申请人提供）：认知障碍是抗癫痫药物最常见的副作用之一，也是停止治疗的常见原因，尤其是老年人。由于药代动力学的个体差异和对不良反应的敏感性，很难预测哪些患者有发生药物引起的神经心理功能恶化的风险。该项目的目标是表征托吡酯 (TPM) 药代动力学、药物基因组学和认知功能之间的关系，以便预测哪些患者在接受包含 TPM 的治疗方案时最有可能表现出严重的认知缺陷。年龄和基因型对 TPM 药代动力学的影响将使用新型稳定标记（非放射性）静脉 TPM 制剂来确定，并且将评估单点血浆浓度方法预测个体随后的全身药物暴露的效用。认知功能将取决于年龄和 TPM 治疗持续时间的影响。将药代动力学和神经心理学测量相关联，以确定可用于预测 TPM 引起的认知障碍风险的因素。这种方法不仅有助于优化 TPM 治疗，而且可以应用于其他 AED，更广泛地应用于其他神经活性药物。如果成功，它将改变当代将药物推至最大耐受剂量的常见做法。