CHILDHOOD ABSENCE EPILEPSY RX, PK-PD-PHARMACOGENETICS

儿童失神癫痫 RX、PK-PD-药物遗传学

• 批准号: 7950599
• 负责人: ANGUS A WILFONG
• 金额: $ 0.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950599
• 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 Research; 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; 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; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Pharmacotherapy; Phenotype; Physicians; Population; Predisposing Factor; Psychosocial Influences; Quality of life; Questionnaires; Randomized; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Relapse; Research; Research Personnel; Resources; Seizures; 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; Weight Gain; base; clinical phenotype; comparative trial; design; drug clearance; drug efficacy; experience; gastrointestinal; indexing; lamotrigine; meetings; neuropsychological; outcome forecast; performance tests; pharmacokinetic model; prospective; psychosocial; response; success; treatment strategy; 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. 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. 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). 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.

该副本是使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，这是调查员的机构。 假设1：可以将单个抗惊厥药鉴定为具有短期效率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结果患者在AED有效AY中观察到的可变性i）来自可识别的药物遗传学（PG）因素，从而影响药物反应（癫痫发作控制）和药物暴露以及II）以及可识别的不可遗忘的宿主因素。 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因素，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。 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）持久性或缓解持续性癫痫发作（临床，过度换气引起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，药物与药物相关的a = 15％的病人或a = 15％的病人/a = 15％的病人/iv）/iiV/iv）/iiV/iiV（IIV）/iiV（IIV）/IV（IV）/IV（IIV）/IV（IIV） 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t型钙通道AED结合亚基基因的影响对使用16周双盲访问（授予特定AIM 2A）的癫痫发作率的AED有效性的影响。 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效率的影响。 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效率的预测能力。 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，丙丙酸代谢物和临床因素对丙抗酸相关的多余体重增加的基因的基因中常见多态性变异的影响，使用遇到的两名患者使用研究标准增加了体重增加的患者（A = 15％的BMI量度增加），将其降低（量度增加）。 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％。儿童缺勤癫痫（pyknolepsy）的特征是经常（每天几至多个），否则在一个正常的患有脑电图的儿童中癫痫发作通常表现出3 Hz双侧，同步，对称的尖峰波模式，具有正常的背景活动（3-5）。 CAE患者通常被视为“良性”癫痫综合症，表现出对治疗的反应，裸露的认知缺陷，遇到意外损伤率升高，表现出长期的心理社会难度，并且具有可变的缓解率。与其他癫痫类似，针对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可接受平衡。 根据短期临床试验，三个AED（ETX），Lamotrigine（LTG），丙戊酸（VPA） - 在缺席癫痫发作方面有效地有效。但是，它们的长期有效性尚不清楚，它们的毒性特征是明显的，并且它们对儿童发展中神经系统的长期影响并没有很好地研究。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的有效性和毒性的生物学基础，从而为从基于经验的治疗策略转变为生物学理性疾病/综合征特定的治疗策略提供了重要的机会。 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，最低的治疗限制毒性事件），以及b）确定AED反应中个人间变异的药物遗传学和其他非遗殖因素。 ETX，LTG和VPA作为初始单一疗法的随机，双盲比较试验将使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，普遍的补体癫痫发作（Grand Mal）和CAE被广泛接受，并且每个人都具有易于识别的表型，从而最大程度地降低了传染性诊断的可能性。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，这些问题还没有很好地研究。不完全的癫痫发作控制可能具有明显的后遗症，AED的不良反应会汇总合并症。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）（AED），具有在缺席的情况下具有有效性的受控临床试验证据。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的长期有效性和耐受性。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是基于CAE的当前综合征定义和员工从失败设计中长期自由的自由，该临床持续时间i）对免于癫痫发作的自由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了解CAE中对AED差异反应的分子基础的差距。 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受降低药物清除率和较高的全身性暴露，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％的儿童可能会在lamotrigine（LTG）治疗上产生限制皮疹，因此鉴定系统性LTG暴露率增加与皮疹之间的关联可能允许药代动力学引导剂量升级。 自从9％-44％的儿童发育治疗限制与丙戊酸（VPA）相关的体重增加以来，鉴定临床因素（营养或运动）代谢（丙戊酸代谢产物的模式）（模式）或遗传因素或遗传因素（多态性）（在基因中编码的多态性和与蛋白质相关的基因化剂量均与蛋白质化相关的基因化，以允许体重增加的体重，而蛋白质的体重增加的体重则是未来的，并且是蛋白质的重量。 治疗。