Childhood Absence Epilepsy Rx, PK-PD-Pharmacogenetics

说明(由申请人提供)：儿童失神癫痫(CAE)的最佳治疗尚未确定，这是一种常见的儿科癫痫综合征，影响到所有癫痫儿童的10%-15%，治疗反应的个体差异的基础尚未确定。CAE患者通常被误认为是良性癫痫综合征，表现出对治疗的不同反应，表现出认知障碍，并表现出长期的心理社会困难。这项建议的目标是：1)确定对CAE儿童产生和维持最高的癫痫控制率和最低的治疗限制毒性的抗癫痫药物(AED)，以及2)确定AED疗效和毒性个体间差异背后的药物遗传和非遗传因素。乙琥胺(ETX)、拉莫曲吉(LTG)和丙戊酸盐(VPA)作为初始单一疗法，将以无失败率为主要终点，对CAE儿童进行随机双盲对照试验。美国的20个网站将在3年内招收473名2-13岁的儿童。治疗的成功将被定义为癫痫控制和短期和长期耐受性的综合。将研究每种AED对认知(特别是注意力)、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)方法确定的个体系统性药物暴露，将确定患者之间药物处置的变异性对AED疗效和毒性的影响，并将用于选择药物代谢酶的药物遗传学(PG)相关研究。我们将研究T型钙通道α1G、α1H、α1I亚单位编码基因的多态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PG、PK和出现LTG相关皮疹的患者的临床特征、VPA导致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)。这项研究将确定提供最大可能的癫痫控制以及最好的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PG和AED反应中患者间变异的非遗传因素，这一建议将形成基于综合征的AED治疗的药物理性方法的基础。通过这项研究获得的知识将导致对CAE儿童的个体化治疗，这可能在一定程度上可推广到其他儿童和成人癫痫发作障碍。

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.