Treatment of status epilepticus and refractory status epilepticus with intravenous topiramate.

摘要 癫痫持续状态(SE)是一种常见的神经系统急症，约有三分之一的病例对一线和二线抗癫痫药物(ASM)无效，从而进展为难治性SE(RSE)。RSE患者有严重的神经系统发病率和死亡率风险。最近完成的由美国国立卫生研究院资助的SE治疗试验(ESETT)强调了改进SE疗法的必要性。在这项研究中，50%对一线药物(即苯二氮卓类药物；BDZ)无效的人对常用的静脉注射(iv.)也无效。二线药物(如磷苯妥因、丙戊酸盐或左乙拉西坦(LEV))。因此，改进的二线可注射ASM比目前可用的可注射ASM更有可能终止SE，因此是一个重要的未得到满足的医疗需求。在目前可用的ASM中，托吡酯(TPM)是一种有吸引力的药物，用于评估难治性SE的癫痫抑制作用，因为(1)它的多模式作用机制，(2)在高度耐药的SE病例中静脉给药的有利数据，以及(3)它的神经保护潜力。口腔和鼻胃管TPM可以改善RSE和超难治性SE(SRSE，一种癫痫持续超过24小时的情况)，许多其他ASM都失败了。然而，TPM不能用于临床静脉注射。给药，这是SE治疗的首选途径。我们(PrevEp，Inc.)开发了一种新颖的、受知识产权保护的静脉注射。TPM配方(PrevEp004)使用FDA批准的赋形剂葡甲胺，提供出色的静脉注射。耐受性好，可跨年龄快速给药治疗SE/RSE。我们现在建议测试PrevEp004容量以终止SE/RSE。我们将(1)测量静脉注射的耐受性和有效性。TPM(PrevEp004)与静脉注射的比较在已建立的SE的大鼠锂-匹罗卡品模型中，使用BDZ模拟实际临床情况，采用随机、盲法设计，连续视频脑电监测治疗结果；(2)测量最有效剂量静脉注射的血浆和脑药代动力学(PK)。为确定TPM在大鼠体内的有效血药浓度和脑内药物浓度进行临床靶向试验；(3)进一步优化新型静脉注射给药方案。PrevEp004(静脉注射)配方TPM)，并建立了静脉注射的GMP制造工艺。能够提供临床试验的配方；(4)评价静脉注射的毒性。通过静脉注射进行符合GLP的多剂量毒性研究，在大鼠中制备TPM制剂。PrevEp004的管理；以及(5)准备与FDA的IND前会议，以使用从AIMS 1-4获得的数据进行临床试验。匹罗卡品的实验和PK研究将由弗吉尼亚大学的古德金博士完成。药物开发将与UCD的罗加夫斯基博士一起完成。预期结果：在两年的资金资助内，我们将(A)在病因学上真实的SE大鼠模型中测试PrevEp004的耐受性和有效性；(B)开发合适的PrevEp004配方并鉴定其安全性；以及(C)召开IND前会议，以使未来能够在志愿者和SE/RSE患者中进行I期和ILA计划，作为迈向第一项人类概念验证(PoC)研究的一步，这将是后续SBIR II期应用的基础。除了本提案的范围外，PrevEp004也可以作为静脉注射。TPM替代物，可用于应用TPM治疗癫痫或偏头痛的患者(在美国为200万人)无法耐受肠道药物治疗(例如，胃肠道手术后)。

Abstract Status epilepticus (SE) is a common neurologic emergency that fails to respond to first- and second-line anti-seizure medications (ASMs) in about one third of instances, thus progressing to refractory SE (RSE). Patients with RSE are at grave risk for neurological morbidity and mortality. The recently completed NIH-funded Established SE Treatment Trial (ESETT) highlights the need for improved SE therapies. In that study, >50% of people who failed to respond to the first line agent (i.e. a benzodiazepine; BDZ also failed to respond to the commonly used intravenous (i.v.) second-line agents (e.g. fosphenytoin, valproate, or levetiracetam (LEV)). An improved second-line injectable ASM, with higher likelihood to terminate SE than presently-available injectable ASMs, is thus an important unmet medical need. Of the currently available ASMs, topiramate (TPM) is an attractive medication to evaluate for seizure suppression in treatment-resistant SE given (1) its multimodal mechanism of action, (2) favorable data from parenteral administration in cases of highly resistant SE, and (3) its potential for neuroprotection. Oral and nasogastric tube TPM can ameliorate RSE and super-refractory SE (SRSE, a condition where seizures persist for more than 24 hours) where numerous other ASMs have failed. Yet, TPM is not clinically available for i.v. administration, which is the route of choice in SE treatment. We (PrevEp, Inc.) developed a novel, intellectual property-protected i.v. TPM formulation (PrevEp004) using the FDA-approved excipient meglumine, which provides excellent i.v. tolerability and enables rapid TPM administration across ages for treatment of SE/RSE. We now propose to test the PrevEp004 capacity to terminate SE/RSE. We will (1) measure the tolerability and efficacy of i.v. TPM (PrevEp004) in comparison to i.v. LEV in the rat lithium-pilocarpine model of established SE, following treatment with a BDZ to mimic a realistic clinical situation, using a randomized, blinded design with continuous video EEG monitoring of treatment outcome; (2) measure plasma and brain pharmacokinetics (PK) of the most effective dose of i.v. TPM in rats in order to determine effective drug plasma and brain concentrations to target in clinical trials; (3) further optimize the novel i.v. formulation of PrevEp004 (i.v. TPM), and establish a GMP manufacturing process for the i.v. formulation to enable clinical trial supply; (4) Evaluate the toxicity of the i.v. TPM formulation in rats by conducting a GLP compliant multiple dose toxicity study with i.v. administration of PrevEp004; and (5) prepare a pre-IND meeting with the FDA to enable clinical trials using data obtained from aims 1-4. The pilocarpine experiments and PK studies will be done by Dr. Goodkin at UVA. The pharmaceutical development will be done with Dr. Rogawski at UCD. Expected outcome: Within two years of funding we will (a) test PrevEp004 tolerability and efficacy in an etiologically realistic rat SE model; (b) develop a suitable PrevEp004 formulation and characterize its safety; and (c) conduct a pre-IND meeting to enable the future conduct of a phase I and Ila program in volunteers and SE/RSE patients as a step toward the first-in-human proof of concept (PoC) study, which will be the basis of a subsequent SBIR phase II application. Beyond the scope of this proposal, PrevEp004 may also serve as an i.v. TPM replacement that can be used in instances where patients (>2 million in US) who apply TPM for seizure or migraine management cannot tolerate enteric medication (e.g. after gastrointestinal surgery).