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，约三分之一的病例对一线和二线抗癫痫药物（ASM）无效，因此进展为难治性SE（RSE）。RSE患者存在神经系统发病率和死亡率的严重风险。最近完成的NIH资助的既定SE治疗试验（ESETT）强调了改进SE疗法的必要性。在该研究中，>50%对一线药物（即苯二氮卓类; BDZ也对常用的静脉内（i. v.）二线药物（如磷苯妥英、丙戊酸盐或左乙拉西坦（LEV））。因此，与目前可用的可注射ASM相比，改善的二线可注射ASM终止SE的可能性更高，是一个重要的未满足的医疗需求。在目前可用的ASM中，托吡酯（TPM）是一种有吸引力的药物，可用于评价治疗难治性SE的癫痫发作抑制作用，因为（1）其多模式作用机制，（2）在高度耐药SE病例中胃肠外给药的有利数据，以及（3）其神经保护潜力。口服和鼻胃管TPM可以改善RSE和超难治性SE（SRSE，癫痫发作持续超过24小时），其中许多其他ASM都失败了。然而，TPM在临床上不可用于静脉内给药，静脉内给药是SE治疗的选择途径。我们（PrevEp，Inc.）使用FDA批准的赋形剂葡甲胺开发了一种新型的、受知识产权保护的静脉注射TPM制剂（PrevEp 004），该制剂具有优异的静脉注射耐受性，并能够跨年龄快速给予TPM治疗SE/RSE。我们现在建议测试PrevEp 004终止SE/RSE的能力。我们将（1）测量静脉注射TPM的耐受性和疗效（PrevEp 004）与静脉注射LEV相比，在建立SE的大鼠锂-匹鲁卡品模型中，在用BDZ治疗以模拟现实临床情况后，使用随机化、设盲设计，连续视频EEG监测治疗结果;（2）测量大鼠中最有效剂量的静脉内TPM的血浆和脑药代动力学（PK），以确定临床试验中有效的药物血浆和脑浓度;（3）进一步优化PrevEp 004的新型静脉注射制剂（i. v. TPM），并建立i. v.制剂的GMP生产工艺，以实现临床试验供应;（4）通过用静脉内施用PrevEp 004进行符合GLP的多剂量毒性研究来评估静脉内TPM制剂在大鼠中的毒性;和（5）准备与FDA的IND前会议，以便使用目标1-4获得的数据进行临床试验。毛果芸香碱实验和PK研究将由Goodkin博士在UVA进行。药物开发将在UCD与Rogawski博士完成。预期成果：在资助的两年内，我们将（a）在病因学上真实的大鼠SE模型中测试PrevEp 004的耐受性和功效;（B）开发合适的PrevEp 004制剂并表征其安全性;和（c）进行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IIa期项目，作为向首次人体概念验证（proof of concept，IND）研究迈出的一步，这将是随后SBIR第二阶段应用的基础。在本提案的范围之外，PrevEp 004还可以作为静脉注射TPM替代品，可用于应用TPM治疗癫痫或偏头痛的患者（在美国> 200万）不能耐受肠道药物（例如胃肠道手术后）的情况。

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).