Childhood Absence Epilepsy Rx, PK-PD-Pharmacogenetics

描述（由申请人提供）：儿童缺乏性癫痫（CAE）是一种常见的儿童癫痫综合征，影响10-15%的癫痫患儿，目前尚未确定儿童缺乏性癫痫（CAE）的最佳治疗方法，以及个体间治疗反应差异的基础。CAE患者通常被误认为是良性癫痫综合征，对治疗表现出不同的反应，表现出认知缺陷，并表现出长期的社会心理困难。本提案的目的是：1)确定抗癫痫药物（AED）产生并维持最高的癫痫控制率，以及CAE患儿最低的治疗限制性毒性发生率，2)确定AED疗效和毒性个体间差异的药理学和非遗传因素。将以无失败率为主要终点，在CAE患儿中进行一项随机、双盲比较试验，将埃索昔胺（ETX）、拉莫三嗪（LTG）和丙戊酸钠（VPA）作为初始单药治疗。在美国的20个站点将在3年的时间里招募473名2- 13岁的儿童。治疗成功将被定义为癫痫发作控制和短期和长期耐受性的综合结果。每个AED对认知（特别是注意力）、行为和生活质量的影响将被研究。每个患者的癫痫综合征将通过视频脑电图广泛地进行表型分析。个体全身药物暴露，使用群体药代动力学（pK）方法确定，将确定药物处置的患者间变异性对AED疗效和毒性的影响，并将用于选定药物代谢酶的药效学（pG）相关研究。将研究T型钙通道α 1g、α 1h、α 1i亚基编码基因多态性变异在治疗反应中的作用。将研究每种AED最常见的治疗限制的潜在预测因素，包括出现LTG相关皮疹、VPA诱导的体重增加或神经认知技能受损的证据的患者的pG、pK和临床概况（所有AED的潜在限制）。本研究将确定能够最大可能控制癫痫发作的AED，以及最佳的短期和长期耐受性。通过全面定义癫痫发作的表型谱，以及pG和非遗传因素，这些因素是AED反应的患者间变异性的基础，该建议将形成基于综合征的AED治疗的药理学合理方法的基础。本研究获得的知识将导致CAE儿童的个体化治疗，这可能在一定程度上推广到其他儿童和成人癫痫疾病。

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.