Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures
Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures
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DOI：
10.1111/j.1528-1167.2012.03543.x
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发表时间：
2013-01-01
期刊：
影响因子：
5.6
通讯作者：
Rudd, G. David
中科院分区：
文献类型：
--
作者：
Fountain, Nathan B.;Krauss, Gregory;Rudd, G. David
目的：在未接受过拉考沙胺治疗的部分性癫痫发作成人患者中，检查通过单次静脉负荷剂量快速启动连续性拉考沙胺，随后每日两次口服拉考沙胺的安全性和耐受性。研究方法：这项开放标签、多中心试验招募了正在服用12种抗癫痫药物（AED）的癫痫患者，分为4个连续队列，每个队列25名受试者。在15分钟内静脉注射拉考沙胺负荷剂量（200、300或400 mg），12小时后开始口服给药，每日两次，持续6.5天。第一个队列给予拉考沙胺200 mg/天，随后是300 mg/天的队列，然后是400 mg/天的队列。在入组下一个最高剂量水平前，评价每个队列的结果。第四个队列入组了具有临床可接受的安全性和耐受性结果的最高剂量患者。安全性评价包括治疗后出现的不良事件（TEAE）、患者因TEAE退出研究以及生命体征、12导联心电图（ECG）研究、实验室参数和临床检查的变化。还评价了输注后拉考沙胺的血浆浓度。关键发现：共入组100例患者，每个队列25例。重复队列的负荷剂量为300 mg;因此，25例患者入组200 mg/天组，50例患者入组300 mg/天组，25例患者入组400 mg/天组。大多数TEAE发生在输注后前4小时内;该时间段内的剂量相关TEAE（发生率=10%）包括头晕、嗜睡和恶心。7例患者退出，均因TEAE：合并300 mg组3例（6%），400 mg组4例（16%）;其中4例患者在输注后4小时内停药。最常见的导致停药的TEAE（总体发生率>1%）为头晕（6%）、恶心（5%）和呕吐（3%）。未观察到ECG、临床实验室参数或生命体征较基线的临床相关变化模式。血浆谷浓度表明，单次静脉负荷剂量可达到接近稳态的拉考沙胺浓度。重要性：拉考沙胺初治患者在15分钟内给予200和300 mg拉考沙胺静脉负荷剂量，随后口服拉考沙胺，耐受性良好。由于剂量相关TEAE的发生率较高，400 mg负荷剂量的耐受性较差。这些结果支持快速启动连续性拉考沙胺治疗的可行性。
Purpose: To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. Methods: This open-label, multicenter trial, enrolled patients with epilepsy who were taking 12 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. Key Findings: A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence =10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. Significance: Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment.