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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 抽象的 假设 假设1：可以将单个抗惊厥药鉴定为具有短期疗效一级证据的三种抗惊厥药中的最佳初始单药治疗（ETX，LTG和VPA）。 假设2：CAE结果患者的AED效率ACY中观察到的可变性i）来自可识别的药物遗传学（PG）因子，从而影响药物反应（癫痫发作控制）和药物暴露以及II）以及可识别可遗传的宿主因素。 假设3：CAE结果患者的AED耐受性观察到的可变性i）来自可识别的PG因子，导致药物反应（毒性）和药物暴露以及ii）以及可识别的非可雄性宿主因素。 具体目标 主要目标 确定最有效的初始单药治疗（在乙糖胺，拉莫三嗪和丙戊酸）中，使用临床试验的双盲部分中使用失败率的儿童缺席癫痫病儿童。我们假设单个抗惊厥药的有效性至少要比其他两种抗惊厥药高20％。双重盲区期间的治疗失败将被定义为i）任何持续时间的普遍性隆隆性癫痫发作，ii）持续或持续性癫痫发作的持久性或复发性（临床，换通量诱导的癫痫发作或电学癫痫发作），iii III），iii）药物相关的与药物相关的全身性毒性（例如，药物相关的a = 15％的患者或a = 15％的患者/iv）/iv a = 15％的病理/iiv）/iv/iv/iv（IV）目标1A）。 次要目标 将有多个次要目标，包括： 1。使用遗漏错误和Conners持续性能测试的总体指数（OI）评估单一疗法对认知（注意）的影响（注意）和Kiddie持续绩效测试（授予特定AIM 1B）。 2。使用儿童行为检查清单中的T得分评估单一疗法对生活质量和生活质量的影响，以及儿童癫痫问卷的生活质量的结果（授予特定目标1B）。 3。评估t型钙通道AED结合亚基基因或AED-efflux转运蛋白ABCB1基因对使用16周双盲访问的癫痫发作率（授予特定AIM 2A）的钙通道AED结合亚基基因ABCB1基因ABCB1基因ABCB1基因的影响（特定于特定于AIM 2A）。 4.使用16周双盲访问（授予特定AIM 2B），使用无癫痫发作率评估AED系统性暴露对AED疗效的影响。 5。使用16周双盲访问（特定于AIM 2C），使用无癫痫发作率评估临床因素对AED疗效的预测能力。 6。评估CYP 3A4/5基因中常见多态性变化对乙糖酰胺暴露和胃肠道副作用的影响，该术使用乙糖酰亚胺暴露在胃肠道副作用或b）在16周双盲访问时测量a）在没有胃肠道副作用的患者的16周双盲访问时（授予特定于胃肠道特定特定的目标3A）。 7。评估常见多态性变异（在UGT1A4基因中）对使用lamotrigine暴露的暴露lamotrigine暴露对拉莫三嗪暴露和与拉莫三嗪相关的皮疹的影响，既是a）在皮疹或b）时在16周时在16周的双重盲目拜访时，对没有皮疹的患者（授予特定的AIM 3B）。 8。评估编码丙戊酸药物代谢酶，丙丙酸代谢物谱和临床因素对丙二甲基酸相关的过度体重增加的基因中常见多态性变异的影响，使用这两种患者使用这两种患者遇到体重增加的患者（a = 15％的体重增加），varproic酸相关的体重增加过度增加（BMI降低了3％）或BMI量度的增强。 iii。 背景和意义 儿童缺勤癫痫（CAE）是一种常见的，临床同质的，良好的儿童发作综合征，占所有儿童癫痫的10-15％。儿童的缺席癫痫（pyknolepsy）的特征是在原本正常的患有脑电图的正常儿童中频繁（每天几至多）癫痫发作通常表现为具有正常背景活动的3 Hz双侧，同步，对称尖峰波模式（3-5）。 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，遇到意外损伤率升高，表现出长期的心理社会困难，并具有可变的缓解率。与其他癫痫类似，CAE儿童的当前治疗方法是经验性的：基于有限的临床试验数据，选择了抗癫痫药（AED），然后滴定至可接受的癫痫发作控制和副作用的平衡。 根据短期临床试验，三个AED（ETX），Lamotrigine（LTG），丙戊酸（VPA） - 可有效地防止癫痫发作。但是，它们的长期疗效尚不清楚，它们的毒性特征是不同的，并且对儿童发展的神经系统的长期影响尚未得到很好的研究。一项比较这些AED的随机临床试验，不仅关注癫痫发作控制，而且集中在耐受性，神经心理功能和生活质量上，可以弥合我们对CAE儿童最佳初始治疗的知识差距。这样的试验提供了一个理想的框架，可以使用先进的遗传，药代动力学和临床表型技术研究AED的生物学基础，从而提供了从基于经验的治疗策略转变为生物学上有理于理性疾病/综合征特定治疗策略的重要机会。 该提案的目标是a）确定针对患有CAE的儿科患者的最佳（最高癫痫发作率，限制限制治疗毒性的最低发病率，b）确定AED反应中个人间变异的基础药物遗传学和其他非遗殖因素的初始AED。 ETX，LTG和VPA作为初始单一疗法的随机双盲比较试验将利用从故障率作为主要终点的自由进行。患者将进行广泛的基因分型和表型。 确定CAE的最佳治疗（特定目标1） 缺席癫痫发作的定义，广义的隆隆声癫痫发作（Grand Mal）和CAE被广泛接受，每个人都具有易于识别的表型，从而最大程度地降低了误诊的可能性。该小儿癫痫综合征定期诊断和治疗儿科神经病学家。患有CAE的儿童有多个医疗和社会心理问题，这些问题尚未得到很好的研究。不完全的癫痫发作控制可能具有明显的后遗症，AED的不良反应会加剧合并症。选择了术毒素（ETX），拉莫三嗪（LTG），丙戊酸（VPA）进行研究，因为这些是唯一的抗癫痫药（AED），具有在缺席的情况下具有控制疗效的控制临床试验证据。然而，迄今为止，还没有研究在一项前瞻性随机对照临床试验中检查这些AED的长期疗效和耐受性。对ETX，LTG和VPA的先前研究具有明显的方法论缺陷，限制了鉴定CAE最佳初始治疗的能力。我们提出的临床试验基于CAE的当前综合征定义，并采用了较长的持续时间，从失败设计中使用了持续的自由，i）对免于癫痫发作的自由定义严格定义为治疗成功的定义以及II）ii）短期和长期治疗限制药物毒性，以确定CAE的最佳治疗（特定目标1A）。总体而言，迄今为止，CAE中的临床试验尚未充分纳入对AED对认知（尤其是注意），行为或生活质量的影响。我们提出的临床试验将连续评估AED对认知（特别是注意），行为和癫痫特异性HRQOL的影响，以识别临床医生可以在为CAE患者选择最佳治疗的AED之间的差异。 （特定目标1b） 影响AED功效的药物遗传学，药代动力学和临床因素（特定目标2） 了解药物遗传学，药代动力学和临床因素以及治疗反应之间的关系将弥合我们在了解如何最好使用AED来治疗CAE儿童的知识方面的差距，并将为未来的治疗个性化构成基础。我们提出的对CACNA1G，CACNA1H和CACNA1I基因中多态性之间关系的研究（对于T型钙通道的A1G，A1H和A1I亚基的代码）与AED治疗的反应是基于对T-Type Cancarels AED药理的基本药理学的基于AED治疗的反应。这项研究将弥合我们对CAE中对AED差异反应的分子基础知识的差距。 ETX，VPA和LTG的种群药代动力学模型将对药物处置的室内变异性及其对药物反应和毒性的影响提供全面的理解。这些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，但存在多种缺勤性癫痫发作的亚型，以及基线间歇性脑电图模式的可识别差异。尚未对亚型，对治疗和预后的反应进行全面分析。 限制治疗的药物遗传学，药代动力学和临床因素（特定目标3） +由于20％-33％的儿童最终会经历胃肠道副作用（ETX），因此鉴定遗传因素易于降低药物清除率和较高的全身性暴露，这些暴露可能与胃肠道副作用相关，这将允许对AED选择的合理个性化。 +由于10％-12％的儿童可能会对拉莫三嗪（LTG）治疗产生限制皮疹，因此鉴定系统性LTG暴露率增加与皮疹之间的关联可能会允许药代动力学引导剂量升级。 +由于9％-44％的儿童发展了限制与丙戊酸（VPA）相关的治疗，因此鉴定临床因素（营养或运动）代谢（丙戊酸代谢产物的模式）（丙丙酸代谢产物的模式）或遗传因素（遗传学因素）（在基因中编码为VPA代谢enzymes或Cherected a coseption for Chorty for for Shower的基因中的多态性）将允许进行体重增加的体重增加。