Childhood Absence Epilepsy Rx, PK-PD-Pharmacogenetics

儿童失神癫痫 Rx，PK-PD-药物遗传学

• 批准号: 7941427
• 负责人: TRACY A GLAUSER
• 金额: $ 200万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941427
• 关键词: 13 year old; Absence Epilepsy; Accidental Injury; Accounting; Adult; Adverse effects; Affect; Age; Anticonvulsants; Antiepileptic Agents; Attention; Behavior; Benign; Binding; CYP2B6 gene; CYP2C19 gene; CYP2C9 gene; CYP2E1 gene; Calcium Channel; Child; Childhood; Clinical; Clinical Trials; Clinical Trials Design; Code; Cognition; Cognitive deficits; Correlative Study; Coupled; Data; Disease; Disease remission; Double-Blind Method; Drug Exposure; Drug Kinetics; 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; Patients; Pattern; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Population; Quality of life; Randomized; Randomized Clinical Trials; 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; common treatment; comparative trial; cytochrome P-450 CYP2A6 (human); drug efficacy; gastrointestinal; lamotrigine; neuropsychological; programs; psychosocial; response; skills; success; time use; treatment strategy; 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）：儿童失神癫痫 (CAE) 是一种常见的小儿癫痫综合征，影响所有癫痫儿童的 10-15%，并且治疗反应存在个体间差异，其最佳治疗方法已没有被定义。 CAE 患者通常被误认为是一种良性癫痫综合征，其对治疗的反应各不相同，表现出认知缺陷，并表现出长期的心理社会困难。该提案的目标是：1) 确定抗癫痫药物 (AED)，该药物能够产生并维持最高的癫痫发作控制率以及最低的治疗发生率，限制 CAE 儿童的毒性，2) 确定药物遗传学AED 功效和毒性的个体差异背后的非遗传因素。将以无失败率作为主要终点，对患有 CAE 的儿童进行一项随机、双盲比较试验，将乙昔酰亚胺 (ETX)、拉莫三吉 (LTG) 和丙戊酸 (VPA) 作为初始单一疗法。美国的 20 个地点将在 3 年时间内招收 473 名 2 至 13 岁的儿童。治疗成功将被定义为癫痫控制和短期和长期耐受性的综合结果。我们将研究每种 AED 对认知（尤其是注意力）、行为和生活质量的影响。每个患者的癫痫综合征将通过视频脑电图进行广泛的表型分析。使用群体药代动力学 (pK) 方法确定的个体全身药物暴露将定义患者间药物处置差异对 AED 疗效和毒性的影响，并将用于选定药物代谢酶的药物遗传学 (pG) 相关研究。将研究编码 T 型钙通道的 α1G、α1H、α1I 亚基的基因中的多态性变异在治疗反应中的作用。 将研究可能预测每种 AED 最常见治疗局限性的因素，包括发生 LTG 相关皮疹的患者的 pG、pK 和临床特征、VPA 引起的体重增加或神经认知技能受损的证据（所有 AED 的潜在局限性）。这项研究将确定能够最大程度地控制癫痫发作并具有最佳短期和长期耐受性的 AED。 通过全面定义失神发作的表型谱以及导致患者间 AED 反应差异的 pG 和非遗传因素，该提案将为基于综合征的 AED 治疗的药理学合理方法奠定基础。通过这项研究获得的知识将有助于对患有 CAE 的儿童进行个体化治疗，这可能在一定程度上推广到其他儿童和成人癫痫病。