Childhood Absence Epilepsy Rx, PK-PD-Pharmacogenetics

儿童失神癫痫 Rx，PK-PD-药物遗传学

• 批准号: 7191606
• 负责人: TRACY A GLAUSER
• 金额: $ 311.93万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191606
• 关键词: Absence Epilepsy; Accidental Injury; Accounting; Adult; Adverse effects; Affect; Age; Age-Years; Anticonvulsants; Antiepileptic Agents; Attention; Behavior; Benign; Binding; CYP2B6 gene; CYP2C19 gene; CYP2C9 gene; CYP2E1 gene; Calcium Channel; Child; Childhood; Clinical; Clinical Trials; Code; Cognition; Cognitive deficits; Correlative Study; Coupled; Data; Disease; Disease remission; Double-Blind Method; Drug Exposure; Drug Kinetics; End Point; Enrollment; Enzymes; Epilepsy; Equilibrium; Ethosuximide; Exanthema; Exhibits; Failure; Foundations; Freedom; Genes; Genetic; Genotype; Goals; Human; Incidence; Individual; Integration Host Factors; Knowledge; Lead; Living Wills; Long-Term Effects; Nervous system structure; Neurocognitive; Numbers; Patients; Pattern; Personal Satisfaction; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Population; Quality of life; Randomized; Rate; Research Personnel; Risk; Role; Seizures; Serum Albumin; Site; Syndrome; T-Type Calcium Channels; Techniques; Therapeutic; Toxic effect; Valproic Acid; Variant; Weight Gain; aging nutrition; base; clinical phenotype; comparative trial; cytochrome P-450 CYP2A6 (human); design; drug efficacy; gastrointestinal; lamotrigine; neuropsychological; programs; psychosocial; response; skills; success; time use; trial comparing; valproate

DESCRIPTION (provided by the applicant): The optimal treatment for Childhood Absence Epilepsy (CAE), a common pediatric epilepsy syndrome affecting 10-15% of all children with epilepsy, and the basis for the inter-individual variation in response to therapy, has not been defined. Commonly misperceived as a benign epilepsy syndrome, patients with CAE demonstrate variable response to therapy, exhibit cognitive deficits, and demonstrate long-term psychosocial difficulties. The objectives of this proposal are: 1) to identify the anti-epileptic drug (AED) that produces and sustains the highest rate of seizure control coupled with the lowest incidence of treatment limiting toxicity for children with CAE, and 2) to determine the pharmacogenetic and non-heritable factors underlying the inter-individual variation in AED efficacy and toxicity. A randomized, double-blind comparative trial of Ethosuximide (ETX), lamotrigi_ (LTG) and valproate (VPA) as initial monotherapy will be performed in children with CAE utilizing freedom from failure rate as the primary endpoint. Twenty sites in the U.S. will enroll 473 children, 2- 13 years of age, over a 3-year period. Treatment success will be defined as a composite of seizure control and short and long-term tolerability. Each AED's impact on cognition (especially attention), behavior, and quality of life will be studied. Each patient's epilepsy syndrome will be extensively phenotyped with video EEGs. Individual systemic drug exposures, determined using a population pharmacokinetic (pK) approach, will define the impact of interpatient variability in drug disposition on AED efficacy and toxicity, and will be utilized in pharmacogenetic (pG) correlative studies of select drug metabolizing enzymes. The role of polymorphic variation in the genes coding for the alpha1G, alpha1H, alpha1I subunits of the T type calcium channels in response to therapy will be investigated. Factors potentially predictive for the most common treatment limitations of each AED will be studied, including the pG, pK and clinical profiles of patients developing LTG associated rash, VPA induced weight gain or evidence of impaired neurocognitive skills (potential limitation of all AEDs). This study will determine the AED that provides for the greatest likelihood of seizure control coupled with the best short and long term tolerability. By comprehensively defining the phenotypic spectrum of absence seizures along with pG and non-heritable factors that underlie interpatient variability in AED response, this proposal will form the foundation of a pharmacologically rational approach to syndrome based AED therapy. Knowledge gained by this study will lead to individualized treatment for children with CAE that may in part be generalizable to other pediatric and adult seizure disorders.

描述（由申请人提供）：尚未定义为所有患有癫痫患者的儿童的最佳治疗（CAE），一种影响所有患有癫痫患者的儿童的常见小儿癫痫综合征，以及针对治疗的个体间差异的基础。 CAE患者通常被误认为是一种良性癫痫综合征，表现出对治疗的反应可变，表现出认知缺陷并表现出长期的社会心理困难。该提案的目标是：1）确定抗癫痫药（AED）产生并维持最高的癫痫发作率，并确定对患有CAE的儿童的治疗限制毒性的最低发病率，以及2），以确定药物遗传学和非疾病性因素和非疾病因素的相互性变异的有效性和效率上的毒性毒性。将在CAE的儿童中，将在患有失败率的自由的儿童中进行一项乙糖胺（ETX），Lamotrigi_（LTG）和丙戊酸（VPA）的随机双盲比较试验。在3年期间，美国有20个地点将注册473名2-13岁的儿童，2-13岁。治疗成功将定义为癫痫控制和短期和长期耐受性的综合。将研究每个AED对认知（尤其是注意），行为和生活质量的影响。每个患者的癫痫综合征将用视频脑电图广泛表型。使用种群药代动力学（PK）方法确定的个体全身药物暴露将定义药物处置中药物差异对AED功效和毒性的影响，并将用于精选药物代谢酶的药物遗传学（PG）相关性研究。将研究响应治疗中T型钙通道的α1G，α1H，α1i亚基的多态性变异在编码的基因中的作用。 将研究针对每种AED最常见治疗限制的因素，包括开发LTG相关皮疹的患者的PG，PK和临床特征，VPA诱导的体重增加或神经认知技能受损的证据（所有AED的潜在限制）。这项研究将确定提供最大癫痫发作可能性的AED，并结合最佳的短期和长期耐受性。 通过全面定义缺勤性癫痫发作的表型光谱以及PG和非遗产因素，这些因素是AED反应中的室内变异性的基础，该建议将构成基于综合征AED疗法的药理学理性方法的基础。这项研究获得的知识将导致针对CAE儿童的个性化治疗，这可能部分可以推广到其他儿科和成人癫痫病。