Forecasting Topiramate's Effect on Cognitive Function

预测托吡酯对认知功能的影响

• 批准号: 7848420
• 负责人: SUSAN E MARINO
• 金额: $ 3.48万
• 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: 2005-08-11 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848420
• 关键词: ABCB1 gene; Adverse effects; Age; Age-Years; Alleles; Antiepileptic Agents; Area; Blood specimen; Carrier Proteins; Cognitive deficits; Deterioration; Drug Exposure; Drug Formulations; Drug Kinetics; Elderly; Genes; Genetic Polymorphism; Genotype; Goals; Half-Life; Impaired cognition; Individual; Intravenous; Label; Maximum Tolerated Dose; Measures; Methods; Patients; Persons; Pharmaceutical Preparations; Pharmacogenomics; Plasma; Radioactive; Risk; Role; Training; Treatment Protocols; age effect; cognitive function; neuropsychological; novel; older patient; topiramate; young adult

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）：认知障碍是与抗癫痫药有关的最普遍的副作用之一，是停止治疗的常见原因，尤其是在老年人中。由于药代动力学的个体变异性和对不良影响的敏感性，很难预测哪些患者在神经心理学功能中有可能发展药物诱导的恶化。该项目的目的是表征托吡酯（TPM）药代动力学，药物基因组学和认知功能之间的关系，以预测哪些患者在置于包括TPM在内的制度下最有可能表现出明显的认知缺陷。年龄和基因型对TPM药代动力学的影响将使用一种新型的，稳定的标记（非放射性）静脉内TPM配方和单点等离子体浓度方法的实用性来预测个人的随后全身药物暴露。认知功能将被确定为TPM治疗的年龄和持续时间的影响。为了识别可用于预测TPM诱导认知障碍风险的因素，将采取药代动力学和神经心理学指标。这种方法不仅有助于优化TPM疗法，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。如果成功的话，它将改变将药物推向最大耐受剂量的常见当代实践。

项目成果

Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case-control study.

由于精神和认知不良事件而停用唑尼沙胺：一项病例对照研究。

• DOI: 10.1212/wnl.0b013e3181eccfb5
• 发表时间: 2010
• 期刊: Neurology
• 影响因子: 9.9
• 作者: White,JR;Walczak,TS;Marino,SE;Beniak,TE;Leppik,IE;Birnbaum,AK
• 通讯作者: Birnbaum,AK

Pharmacokinetic-Pharmacodynamic Modeling of Intravenous and Oral Topiramate and Its Effect on the Symbol-Digit Modalities Test in Adult Healthy Volunteers.

静脉注射和口服托吡酯的药代动力学-药效学模型及其对成年健康志愿者符号-数字模式测试的影响。

• DOI: 10.1002/jcph.646
• 发表时间: 2016
• 期刊: Journal of clinical pharmacology
• 影响因子: 2.9
• 作者: Lim,ChayNgee;Birnbaum,AngelaK;Brundage,RichardC;Leppik,IloE;Cloyd,JamesC;Clark,Annie;Marino,SusanE
• 通讯作者: Marino,SusanE

Genetic and environmental correlates of topiramate-induced cognitive impairment.

托吡酯引起的认知障碍的遗传和环境相关性。

• DOI: 10.1111/j.1528-1167.2011.03322.x
• 发表时间: 2012
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Cirulli,ElizabethT;Urban,ThomasJ;Marino,SusanE;Linney,KristenN;Birnbaum,AngelaK;Depondt,Chantal;Attix,DeborahK;Radtke,RodneyA;Goldstein,DavidB
• 通讯作者: Goldstein,DavidB