CHILDHOOD ABSENCE EPILEPSY RX, PK-PD-PHARMACOGENETICS

儿童失神癫痫 RX、PK-PD-药物遗传学

• 批准号: 7605869
• 负责人: ANGUS A WILFONG
• 金额: $ 1.23万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605869
• 关键词: ABCB1 gene; Absence Epilepsy; Accidental Injury; Accounting; Adverse effects; Albumins; Anticonvulsants; Antiepileptic Agents; Attention; Behavior; Benign; Bilateral; Binding; Body mass index; CACNA1G gene; Child; Child Behavior; Childhood; Clinical; Clinical Trials; Code; Cognition; Cognitive deficits; Comorbidity; Computer Retrieval of Information on Scientific Projects Database; Controlled Clinical Trials; Data; Diagnosis; Disease; Disease remission; Dose; Double-Blind Method; Drug Efflux; Drug Exposure; Drug Kinetics; Drug effect disorder; Drug toxicity; Drug usage; Electroencephalography; End Point; Enzymes; Epilepsy; Equilibrium; Ethosuximide; Exanthema; Exercise; Exhibits; Failure; Foundations; Freedom; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Grant; Hyperventilation; Incidence; Individual; Institution; Integration Host Factors; Knowledge; Long-Term Effects; Measures; Medical; Metabolic; Modeling; Molecular; Nervous system structure; Neurologist; Nutritional; Parents; Patients; Pattern; Personal Satisfaction; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Pharmacotherapy; Phenotype; Physicians; Population; Predisposing Factor; Quality of life; Questionnaires; Randomized; Randomized Controlled Clinical Trials; Rate; Relapse; Research; Research Personnel; Resources; Score; Seizures; Social Aspects of Cancer; Source; Syndrome; T-Type Calcium Channels; Techniques; Therapeutic; Time; Tonic - clonic seizures; Toxic effect; Treatment Failure; United States National Institutes of Health; Valproic Acid; Variant; Visit; Week; Weight Gain; abstracting; base; clinical phenotype; comparative trial; day; design; desire; drug clearance; drug efficacy; experience; gastrointestinal; indexing; lamotrigine; neuropsychological; outcome forecast; performance tests; pharmacokinetic model; prospective; psychosocial; response; success; trial comparing

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT HYPOTHESIS Hypothesis 1: A single anticonvulsant can be identified as the optimum initial monotherapy among the three anticonvulsants that have Level one evidence of short-term efficacy (ETX, LTG and VPA). Hypothesis 2: The variability observed in AED effic acy in patients with CAE results i) from identifiable pharmacogenetic (pG) factors effecting drug response (seizure control) and drug exposure and ii) from identifiable non-heritable host factors. Hypothesis 3: The variability observed in AED tolerability in patients with CAE results i) from identifiable pG factors effecting drug response (toxicity) and drug exposure and ii) from identifiable non-heritable host factors. SPECIFIC AIMS Primary Objective Identify the most effective initial monotherapy (among ethosuximide, lamotrigine and valproic acid) for children with Childhood Absence Epilepsy using the freedom from failure rate in the double blind portion of the clinical trial. We hypothesize that a single anticonvulsant will be at least 20% more effective than either of the other two anticonvulsants. Treatment failure during the double blind portion will be defined as either i) a generalized tonic clonic seizure of any duration, ii) persistence or relapse of absence seizures (clinical, hyperventilation induced seizures or electrographic seizures), iii) drug related systemic toxicity (e.g., drug related rash or a =15% increase in BMI) or iv) patient/parent/guardian or physician desire for patient to withdraw (Grant Specific Aim 1a). Secondary Objectives There will be multiple secondary objectives including: 1. Assess the effects of monotherapy on cognition (attention) using omission errors and the overall index (OI) of the Conners Continuous Performance Test and the Kiddie Continuous Performance Test (Grant Specific Aim 1b). 2. Assess the effects of monotherapy on behavior and quality of life using t-scores from the Child Behavior Check List, and results from the Quality of Life in Childhood Epilepsy questionnaire (Grant Specific Aim 1b). 3. Assess the effects of common polymorphic variations in T type calcium channel AED binding subunit genes or the AED-efflux transporter ABCB1 gene on AED efficacy using the seizure free rate at the 16 week double blind visit (Grant Specific Aim 2a). 4. Assess the effects of AED systemic exposure on AED efficacy using the seizure free rate at the 16 week double blind visit (Grant Specific Aim 2b). 5. Assess the predictive power of clinical factors on AED efficacy using the seizure free rate at the 16 week double blind visit (Grant Specific Aim 2c). 6. Assess the effect of common polymorphic variations in the CYP 3A4/5 gene on ethosuximide exposure and gastrointestinal side effect using ethosuximide exposure measured either a) at the time of a gastrointestinal side effect or b) at the 16 week double blind visit for patients who did not have gastrointestinal side effect (Grant Specific Aim 3a). 7. Assess the effect of common polymorphic variations (in the UGT1A4 gene) on lamotrigine exposure and lamotrigine related rash using lamotrigine exposure measured either a) at the time of a rash or b) at the 16 week double blind visit for patients who did not have a rash (Grant Specific Aim 3b). 8. Assess the effect of common polymorphic variations in genes coding for valproic acid drug metabolizing enzymes, valproic acid metabolite profiles, and clinical factors on valproic acid-associated excessive weight gain using either percentage of patients meeting study exit criteria for weight gain (a =15% increase in BMI) or BMI percentiles as a measure of weight gain (Grant Specific Aim 3c). III. BACKGROUND AND SIGNIFICANCE Childhood Absence Epilepsy (CAE) is a common, clinically homogenous, well-characterized, childhood-onset syndrome that accounts for 10-15% of all childhood epilepsies. Childhood Absence Epilepsy (pyknolepsy) is characterized by very frequent (several to many per day) absences seizures in an otherwise normal child with an EEG usually demonstrating 3 Hz bilateral, synchronous, symmetrical spike-waves pattern with normal background activity (3-5). Commonly misperceived as a "benign" epilepsy syndrome, patients with CAE demonstrate variable response to therapy, exhibit cognitive deficits, encounter elevated rates of accidental injury, demonstrate long-term psychosocial difficulties, and have variable remission rates. Similar to other epilepsies, the current therapeutic approach for children with CAE is empiric: an antiepileptic drug (AED) is selected based on limited clinical trial data, then titrated to an acceptable balance of seizure control and side effects. Based on short-term clinical trials, three AEDs -- ethosuximide (ETX), lamotrigine (LTG), valproic acid (VPA) - are efficacious against absence seizures. However, their long term efficacy is unknown, their toxicity profiles are distinct, and their long-term effects on the developing nervous system of children have not been well studied. A randomized, clinical trial comparing these AEDs, focusing not only upon seizure control but also on tolerability, neuropsychological functioning and quality of life, can bridge our gap in knowledge as to the optimum initial therapy for children with CAE. Such a trial provides an ideal framework to study the biologic basis for efficacy and toxicity of AEDs using advanced genetic, pharmacokinetic and clinical phenotyping techniques, providing an important opportunity to move from empiric -based therapeutic strategies, to biologically rational disease/syndrome specific treatment strategies. The goals of this proposal are a) to identify the optimal (i.e., highest rate of seizure control, lowest incidence of treatment limiting toxicity) initial AED for pediatric patients with CAE, and b) to determine the pharmacogenetic and other nonheritable factors underlying the inter-individual variation in AED response. A randomized, double blind comparative trial of ETX, LTG, and VPA as initial monotherapy will be performed utilizing freedom from failure rate as the primary endpoint. Patients will be extensively genotyped and phenotyped. Determination Of Optimal Therapy For CAE (Specific Aim 1) The definitions of absence seizures, generalized tonic clonic seizure (grand mal), and CAE are widely accepted and each has an easily recognizable phenotype, minimizing the potential for misdiagnosis. This pediatric epilepsy syndrome is regularly diagnosed and treated by pediatric neurologists. Children with CAE have multiple medical and psychosocial issues that have not been well studied. Incomplete seizure control may have significant sequelae, adverse effects of AEDs can aggravate comorbidities. Ethosuximide (ETX), lamotrigine (LTG), valproic acid (VPA) were selected for study because these are the only antiepileptic drugs (AEDs) with controlled clinical trial evidence of efficacy in absence seizures. No study to date, however, has examined the long-term efficacy and tolerability of these AEDs in a prospective randomized controlled clinical trial. Prior studies of ETX, LTG, and VPA had significant methodological flaws limiting the ability to identify the optimum initial treatment of CAE. Our proposed clinical trial is based on the current syndrome definition for CAE and employs a long duration freedom from failure design that considers i) a stringent definition of freedom from seizures as the definition of treatment success along with ii) short and long term treatment limiting drug toxicities in order to identify the optimal therapy for CAE (Specific Aim 1a). Overall, to date, clinical trials in CAE have not adequately incorporated assessment of AED effect on cognition (especially attention), behavior, or quality of life. Our proposed clinical trial will serially assess each AED's impact on cognition (specifically attention), behavior and epilepsy specific HRQOL to identify differences between AEDs that clinicians can use in selecting optimal therapy for CAE patients. (Specific Aim 1b) Pharmacogenetic, Pharmacokinetic, And Clinical Factors That Impact AED Efficacy (Specific Aim 2) Understanding the relationship between pharmacogenetic, pharmacokinetic and clinical factors and therapeutic response will bridge our gap in knowledge of how best to use AEDs for the treatment of children with CAE, and will form the foundation for the future individualization of therapy. Our proposed study of the relationship between polymorphisms in the CACNA1G, CACNA1H, and CACNA1I genes (that code for the a1G, a1H and a1I subunits of the T-type calcium channel) and the response to AED therapy is based on the basic pharmacology of AED action on T-type calcium channels. This study will bridge our gap in knowledge of the molecular basis for differential response to AEDs in CAE. Population pharmacokinetic models for ETX, VPA and LTG will provide a comprehensive understanding of the interpatient variability in drug disposition and its impact on drug response and toxicity. The models will allow for defining important pharmacogenetic and pharmacodynamic correlations. Although CAE has an easily recognizable phenotype, multiple subtypes of absence seizures exist along with recognizable differences in baseline interictal and ictal EEG patterns. A comprehensive analysis of subtypes, response to treatment and prognosis has not been performed. Pharmacogenetic, Pharmacokinetic And Clinical Factors That Limit Treatment (Specific Aim 3) + As 20%-33% of children ultimately experience gastrointestinal side effects with ethosuximide (ETX), the identification of genetic factors predisposing to decreased drug clearance and higher systemic exposures that may be associated with gastrointestinal side effects would permit rational individualization of AED selection. + Since 10%-12% of children may develop a treatment limiting rash on lamotrigine (LTG) therapy, the identification of an association between rate of systemic LTG exposure increase and rash may allow for a pharmacokinetically guided dose escalation. + Since 9%-44% of children develop treatment limiting weight gain associated with valproic acid (VPA), the identification of clinical factors (nutritional or exercise) metabolic (patterns of valproic acid metabolites) or genetic factors (polymorphisms in genes coding for VPA metabolizing enzymes or albumin) associated with the occurrence of weight gain would permit for rational AED selection and individualization of therapy.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 抽象的 假设 假设 1：在具有短期疗效一级证据的三种抗惊厥药（ETX、LTG 和 VPA）中，单一抗惊厥药可被确定为最佳初始单一疗法。 假设 2：在 CAE 患者中观察到的 AED 疗效的变异性源于 i) 可识别的药物遗传学 (pG) 因素影响药物反应（癫痫控制）和药物暴露，以及 ii) 可识别的非遗传性宿主因素。 假设 3：在 CAE 患者中观察到的 AED 耐受性的变异性源自 i) 可识别的影响药物反应（毒性）和药物暴露的 pG 因素，以及 ii) 可识别的非遗传性宿主因素。 具体目标 主要目标 利用临床试验双盲部分的无失败率，确定对儿童失神癫痫儿童最有效的初始单一疗法（乙舒酰亚胺、拉莫三嗪和丙戊酸）。我们假设单一抗惊厥药的疗效至少比其他两种抗惊厥药高 20%。双盲部分期间的治疗失败将被定义为 i) 任何持续时间的全身强直阵挛发作，ii) 失神发作持续或复发（临床、过度换气引起的癫痫发作或电图癫痫发作），iii) 药物相关的全身毒性（例如，癫痫发作）。 、药物相关皮疹或 BMI 增加 =15%) 或 iv) 患者/家长/监护人或医生希望患者退出（授予具体目标 1a）。 次要目标 将有多个次要目标，包括： 1. 使用遗漏错误以及 Conners 连续表现测试和 Kiddie 连续表现测试（Grant Specific Aim 1b）的总体指数 (OI) 评估单一疗法对认知（注意力）的影响。 2. 使用儿童行为检查表中的 t 分数和儿童癫痫生活质量问卷的结果（授予具体目标 1b）评估单一疗法对行为和生活质量的影响。 3. 使用 16 周双盲访视时的无癫痫发作率来评估 T 型钙通道 AED 结合亚基基因或 AED 外排转运蛋白 ABCB1 基因的常见多态性变异对 AED 疗效的影响（Grant Specific Aim 2a）。 4. 使用 16 周双盲访视的无癫痫发作率评估 AED 全身暴露对 AED 疗效的影响（Grant Specific Aim 2b）。 5. 使用 16 周双盲访视的无癫痫发作率评估临床因素对 AED 疗效的预测能力（Grant Specific Aim 2c）。 6. 使用 a) 出现胃肠道副作用时或 b) 在患者第 16 周双盲访视时测量的乙舒酰暴露量，评估 CYP 3A4/5 基因中常见多态性变异对乙舒酰暴露和胃肠道副作用的影响没有胃肠道副作用（Grant Specific Aim 3a）。 7. 对于没有出现皮疹的患者，使用 a) 皮疹时或 b) 第 16 周双盲访视时测量的拉莫三嗪暴露量，评估常见多态性变异（UGT1A4 基因中）对拉莫三嗪暴露和拉莫三嗪相关皮疹的影响。出现皮疹（Grant Specific Aim 3b）。 8. 使用符合体重增加研究退出标准的患者百分比，评估编码丙戊酸药物代谢酶、丙戊酸代谢物谱和临床因素的常见多态性变异对丙戊酸相关体重过度增加的影响（a = BMI 增加 15%）或 BMI 百分位数作为体重增加的衡量标准（Grant Specific Aim 3c）。 三． 一、背景及意义 儿童失神癫痫 (CAE) 是一种常见、临床同质、特征明确的儿童期发病综合征，占所有儿童癫痫的 10-15%。儿童失神癫痫（紧缩性癫痫）的特点是其他方面正常的儿童非常频繁（每天几次到多次）失神发作，脑电图通常显示 3 Hz 双侧、同步、对称棘波模式，背景活动正常 (3-5) 。 CAE 患者通常被误解为“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，意外伤害发生率升高，表现出长期的社会心理困难，并且缓解率各异。与其他癫痫类似，目前 CAE 儿童的治疗方法是经验性的：根据有限的临床试验数据选择抗癫痫药物 (AED)，然后逐渐调整至癫痫控制和副作用之间可接受的平衡。 根据短期临床试验，三种 AED——乙舒酰亚胺 (ETX)、拉莫三嗪 (LTG)、丙戊酸 (VPA)——对失神发作有效。然而，它们的长期功效尚不清楚，它们的毒性特征也很明显，并且它们对儿童神经系统发育的长期影响尚未得到充分研究。比较这些 AED 的随机临床试验不仅关注癫痫发作控制，还关注耐受性、神经心理功能和生活质量，可以弥补我们在 CAE 儿童最佳初始治疗方面的知识差距。这样的试验提供了一个理想的框架，利用先进的遗传、药代动力学和临床表型分析技术来研究 AED 功效和毒性的生物学基础，为从基于经验的治疗策略转向生物学上合理的疾病/综合征特异性治疗策略提供了重要的机会。 。 该提案的目标是 a) 确定 CAE 儿科患者的最佳初始 AED（即癫痫发作控制率最高、治疗限制毒性发生率最低），以及 b) 确定药物遗传学和其他非遗传性因素-AED 反应的个体差异。将使用无失败率作为主要终点，对 ETX、LTG 和 VPA 作为初始单一疗法进行随机、双盲比较试验。将对患者进行广泛的基因分型和表型分析。 确定 CAE 的最佳治疗（具体目标 1） 失神发作、全身强直阵挛发作（大发作）和 CAE 的定义已被广泛接受，并且每种都有易于识别的表型，从而最大限度地减少误诊的可能性。这种小儿癫痫综合征由小儿神经科医生定期诊断和治疗。患有 CAE 的儿童存在多种尚未得到充分研究的医学和社会心理问题。癫痫发作控制不完全可能会产生严重的后遗症，AED 的不良反应会加重合并症。选择乙昔酰亚胺 (ETX)、拉莫三嗪 (LTG)、丙戊酸 (VPA) 进行研究，因为这些是唯一具有对照临床试验证据证明对失神发作有效的抗癫痫药物 (AED)。然而，迄今为止还没有研究在前瞻性随机对照临床试验中检验这些 AED 的长期疗效和耐受性。先前对 ETX、LTG 和 VPA 的研究存在显着的方法学缺陷，限制了确定 CAE 最佳初始治疗的能力。我们提议的临床试验基于当前 CAE 综合征的定义，并采用长期无失败设计，考虑 i) 无癫痫发作的严格定义作为治疗成功的定义，以及 ii) 短期和长期治疗限制药物毒性以确定 CAE 的最佳治疗（具体目标 1a）。总体而言，迄今为止，CAE 的临床试验尚未充分纳入 AED 对认知（尤其是注意力）、行为或生活质量影响的评估。我们提议的临床试验将连续评估每种 AED 对认知（特别是注意力）、行为和癫痫特定 HRQOL 的影响，以确定 AED 之间的差异，临床医生可以使用这些差异为 CAE 患者选择最佳治疗。 （具体目标 1b） 影响 AED 功效的药物遗传学、药代动力学和临床因素（具体目标 2） 了解药物遗传学、药代动力学和临床因素与治疗反应之间的关系将弥补我们在如何最好地使用 AED 治疗 CAE 儿童方面的知识差距，并将为未来个体化治疗奠定基础。我们提出的 CACNA1G、CACNA1H 和 CACNA1I 基因（编码 T 型钙通道的 a1G、a1H 和 a1I 亚基）多态性与 AED 治疗反应之间关系的研究基于 AED 的基本药理学对T型钙通道的作用。这项研究将弥补我们在 CAE 中 AED 差异反应的分子基础知识方面的差距。 ETX、VPA 和 LTG 的群体药代动力学模型将提供对患者间药物分布差异及其对药物反应和毒性的影响的全面了解。该模型将允许定义重要的药物遗传学和药效学相关性。尽管 CAE 具有易于识别的表型，但存在多种失神发作亚型，并且基线发作间期和发作期脑电图模式存在可识别的差异。尚未对亚型、治疗反应和预后进行全面分析。 限制治疗的药物遗传学、药代动力学和临床因素（具体目标 3） + 由于 20%-33% 的儿童最终会经历乙舒酰亚胺 (ETX) 的胃肠道副作用，因此识别出易导致药物清除率降低和可能与胃肠道副作用相关的较高全身暴露的遗传因素将允许合理个体化 AED 选择。 + 由于 10%-12% 的儿童可能会在拉莫三嗪 (LTG) 治疗中出现限制皮疹的治疗，因此确定全身 LTG 暴露增加率与皮疹之间的关联可能允许药代动力学指导的剂量递增。 + 由于 9%-44% 的儿童正在接受与丙戊酸 (VPA) 相关的限制体重增加的治疗，因此需要确定临床因素（营养或运动）、代谢（丙戊酸代谢物模式）或遗传因素（VPA 编码基因的多态性）与体重增加相关的代谢酶或白蛋白）将允许合理的 AED 选择和个体化治疗。