Rapid dosage titration of levetiracetam in children

STUDY OBJECTIVE: To report our experience with rapid titration of levetiracetam regimens in children and adolescents who were unresponsive to or intolerant of other antiepileptic drugs. METHODS: A retrospective chart review was performed to identify patients with childhood epilepsy who underwent a rapid titration to full doses of levetiracetam in 2 weeks or less. Data regarding demographics, disease characteristics, previous use of antiepileptics, levetiracetam dosage titration schedule, and clinical outcomes were collected and analyzed. RESULTS: Eight children (seven girls, one boy) aged 19 months-17 years were identified. The levetiracetam dosage was titrated to full maintenance doses over 2-14 days (mean 10 days). All patients demonstrated greater than 50% reduction in seizure frequency, with six patients (75%) becoming seizure free. Only one patient experienced a clinically significant adverse event. CONCLUSION: Rapid dosage titration of levetiracetam is feasible and well tolerated in children who require rapid escalation to therapeutic doses.     

左乙拉西坦血药浓度影响因素探讨及参考区间的初步建立

目的建立癫痫患儿左乙拉西坦血药浓度的参考区间,并探讨血药浓度相关的影响因素,为临床个体化用药提供参考。方法收集规律服用左乙拉西坦不少于3个月的0~14岁门诊及住院的332例患儿血样,用高效液相色谱串联质谱(HPLC-MS/MS)法测定左乙拉西坦的血药浓度,分析单用药组、联合用药组及不同性别对左乙拉西坦血药浓度的影响。结果血药浓度数据分析显示,单用药组与联合用药组的左乙拉西坦血药浓度差异无统计学意义(P>0.05)。单用药组男性血药浓度为9.40(5.90~12.50)μg·mL^-1,女性为7.73(5.59~10.42)μg·mL^-1;联合用药组男性血药浓度为9.57(6.82~12.90)μg·ml-1,女性为7.62(5.84~10.40)μg·mL^-1;总用药组男性血药浓度为9.06(5.22~12.40)μg·mL^-1,女性为7.73(5.41~11.20)μg·mL^-1,单用药组与总用药组不同性别间血药浓度差异均有统计学意义(均P<0.05)。本研究总样本左乙拉西坦血药浓度参考区间为2.5~24μg·mL^-1。结论儿童抗癫痫治疗时血药浓度与剂量存在相关性;而性别及联合用药等因素的影响,后续还需扩大样本量进一步研究验证。     

左乙拉西坦与丙戊酸钠用于颞叶癫痫添加治疗的疗效对比

目的：对比左乙拉西坦和丙戊酸钠对6个月单药治疗无效的颞叶癫痫（temporal lobe epilepsy,TLE）患者进行添加治疗的疗效。方法：对使用卡马西平、奥卡西平、拉莫三嗪单药治疗6个月无效的180例TLE患者分别添加丙戊酸钠、左乙拉西坦进行联合治疗,对比两者疗效。结果：卡马西平、奥卡西平、拉莫三嗪单药治疗6个月无效的TLE患者添加左乙拉西坦或丙戊酸钠联合治疗后发作频率有明显降低,其中左乙拉西坦较丙戊酸钠疗效更好,结果有显著性差异（P<0.05）。结论：对使用卡马西平、奥卡西平、拉莫三嗪单药治疗6个月无效的TLE患者,添加左乙拉西坦疗效优于丙戊酸钠。     

妊娠期癫痫患者左乙拉西坦药动学行为变化

目的：系统研究左乙拉西坦（levetiracetam,LEV）在妊娠期癫痫患者体内药动学行为变化,并探究基于LEV血药浓度监测,调整妊娠期癫痫患者的给药方案。方法：回顾性收集2017年1月至2021年7月于中国医科大学附属盛京医院就诊并进行LEV血药浓度监测的妊娠期癫痫患者的临床病历资料,计算孕前至产后LEV的表观清除率（CL）,分析妊娠期癫痫患者LEV的给药方案,并探究妊娠期合并用药对LEV体内药动学行为的影响。结果：对17例单用LEV治疗的妊娠期癫痫患者138次血药浓度监测数据的回顾性分析表明,妊娠期LEV的CL显著增加,与孕前基线相比,在妊娠早期、中期及晚期分别增加了86.39%（P<0.01）、148.30%（P<0.01）和134.69%（P<0.01）,分娩后迅速下降,于产后6周左右恢复至孕前水平。不同妊娠时期LEV给药剂量存在差异,妊娠中、晚期给药剂量较孕前分别增加了44.93%（P<0.01）和96.07%（P<0.01）。妊娠期合用具酶诱导作用的抗癫痫药能够诱导LEV代谢,使LEV的CL增加。结论：妊娠期癫痫患者LEV体内药动学行为变化显著,其CL于妊娠中期达到峰值,分娩后迅速降低。与具酶诱导作用的抗癫痫药合用会增加LEV的CL。定期监测LEV血药浓度可为妊娠期癫痫患者的药物治疗管理提供指导。     

自身对照左乙拉西坦添加治疗耐药性癫痫部分性发作的疗效及安全性

目的:评价左乙拉西坦作为添加剂治疗成人耐药性癫痫部分性发作的疗效和安全性。方法:本试验为单盲、前瞻性研究,27例耐药性癫痫病人在原用药基础上加用安慰剂16 wk,停用安慰剂,再加用左乙拉西坦治疗16 wk,X~2检验比较左乙拉西坦添加期疗效与安慰剂期疗效的差别,并观察其不良反应。结果:左乙拉西坦治疗有效而安慰剂无效的病例13例(48%),安慰剂治疗有效而左乙拉西坦无效的病例5例(19%),左乙拉西坦治疗有效的病例数明显高于安慰剂治疗有效的病例数(P＜0．05)。左乙拉西坦添加治疗期21例(78%)出现不良反应,安慰剂添加期20例(74%)出现不良反应。左乙拉西坦添加治疗期的不良反应主要有情绪异常、头晕、胃肠不适,部分病人有短暂性轻度血白细胞减少,没有病例因严重不良反应退出。结论:左乙拉西坦治疗成人耐药性癫痫部分性发作有效,且不良反应轻,对耐药性癫痫病人是一种有益的选择。     

Clinical pharmacology of levetiracetam for the treatment of epilepsy

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic–clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug–drug interactions have been explored across large adult and pediatric populations. The exposure–response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.     

左乙拉西坦对癫痫患儿骨代谢影响的临床观察

目的:探讨抗癫痫药左乙拉西坦(LEV)对癫痫患儿骨代谢的影响。方法:选择2008年1月—2010年2月期间在唐山市妇幼保健院首发初诊的原发性癫痫患儿30例,予口服LEV治疗。于治疗前和治疗后6个月、12个月分别测定骨密度(BMD)、骨碱性磷酸酶(BAP)、血钙(Ca2+)、血磷(P)、血中碱性磷酸酶(ALP)。对照组为30例未治疗的原发性癫痫患儿,同期检测上述指标。对上述骨代谢指标进行评价。结果:左乙拉西坦治疗前后骨代谢指标差异无显著性(P>0.05)。左乙拉西坦治疗前、治疗后6个月、12个月BMD、BAP、Ca、P、ALP与对照组比较差异无显著性(P>0.05)。结论:短期服用左乙拉西坦(LEV)对癫痫患儿骨代谢无明显影响。     

Changes in medication associated with epilepsy-related hospitalisation: a case-crossover study

AIM: To assess the association between changes in medication and epilepsy-related hospitalisation. METHODS: Data were obtained from the PHARMO Record Linkage System (Jan 1998 to Dec 2002). We conducted a case-crossover study among patients with a first epilepsy-related hospital admission who had continuously used at least one antiepileptic drug (AED) during a 28-week period before admission. For each patient, changes in medication in a 28-day window before hospitalisation were compared with changes in four earlier 28-day windows. Evaluated changes were: changes in AEDs (pattern and dosage), changes in interacting co-medication and changes in non-interacting co-medication (i.e. introduction of non-interacting drugs). The strength of the association between changes in medication and epilepsy-related hospitalisation was estimated using conditional logistic regression analysis and expressed as odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: Out of 1185 patients with a first epilepsy-related hospitalisation, 217 patients met the inclusion criteria. Of the changes in antiepileptic therapy, discontinuation showed a trend towards an increased risk of hospitalisation (OR: 2.57; 95%CI: 0.81-8.17). Drug interactions influencing antiepileptic therapy rarely occurred. Introduction of three or more non-interacting drugs was significantly associated with epilepsy-related hospitalisation (OR: 4.80; 95%CI: 2.12-10.87). Of individual drugs, addition of antimicrobial agents was significantly associated with epilepsy-related hospitalisation (OR: 1.99; 95%CI: 1.06-3.75). CONCLUSIONS: Changes in AED therapy were not significantly associated with epilepsy-related hospitalisation and few drug interactions influencing antiepileptic therapy occurred. However, patients starting three or more new non-AEDs had a nearly five times increased risk of epilepsy-related hospital admission.     

基于FAERS数据库的左乙拉西坦不良事件信号挖掘与分析

目的 通过对抗癫痫药物左乙拉西坦不良事件（ADE）信号的挖掘分析,以期为临床安全合理用药提供参考。方法 采用比例失衡法中的报告比值比法（ROR）和综合标准法（MHRA）对2017年1季度至2021年3季度美国食品药品监督管理局（FDA）不良事件报告系统（FAERS）中左乙拉西坦的ADE报告进行数据挖掘及分析。结果 分析处理数据后共得到622个有效信号,涉及24个系统器官,主要集中在各类神经系统疾病、精神病类、妊娠期及产褥期及围产期状况等方面,发现说明书中未出现的信号累及器官系统有6个。结论 基于FAERS数据库对左乙拉西坦ADE信号挖掘可促进左乙拉西坦的安全、合理使用。     

左乙拉西坦对急性癫痫小鼠海马GABA能神经元电生理的研究

目的:研究癫痫小鼠海马CA1区γ-氨基丁酸(GABA)能神经元电生理变化及使用左乙拉西坦(levetiracetam,Lev)干预治疗后的变化.方法:将FVB-Tg小鼠随机分为正常组、模型组、左乙拉西坦干预组.左乙拉西坦采用灌胃给药.在造模成功后直接断头取脑,制作脑片,在人工脑脊液中孵育后,利用膜片钳技术,进行全细胞记录.结果:与正常组相比,模型组动作电位的绝对不应期延长(P＜0.05),电位能障(Vts-Vr)值上升(P＜0.05),动作电位间距延长(P＜0.05),差异有统计学意义.与模型组相比,左乙拉西坦干预组动作电位的绝对不应期缩短(P＜0.01),电位能障(Vts-Vr)值下降(P＜0.01),动作电位间距缩短(P＜0.01),差异有显著统计学意义.结论:左乙拉西坦组干预后癫痫小鼠海马CA1区GABA能神经元内在特性和编码能力增强,GABA能神经元功能增加可能在癫痫的治疗中起重要作用.     

Levetiracetam: the first SV2A ligand for the treatment of epilepsy

Levetiracetam is a multiple action drug that primarily acts through an interaction with the synaptic vesicle protein 2A. Levetiracetam is the first drug of its kind to be approved for the treatment of epilepsy and is now the most prescribed among the newer antiepileptic drugs. The discovery process identifying levetiracetam's antiepileptic potential was unique because it challenged several dogmas of antiepileptic drug discovery, and thereby encountered skepticism from the epilepsy community. This was contrasted by a very successful development programme leading to rapid regulatory approval by the FDA. The history of levetiracetam proves that a small core group of committed scientists and physicians, who dare to challenge the conventional scientific doctrine, can be successful in bringing to market a truly novel therapy for epilepsy patients.     

Population pharmacokinetics modeling of levetiracetam in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model of levetiracetam in Chinese children with epilepsy.

Methods:

A total of 418 samples from 361 epileptic children in Peking University First Hospital were analyzed. These patients were divided into two groups: the PPK model group (n=311) and the PPK validation group (n=50). Levetiracetam concentrations were determined by HPLC. The PPK model of levetiracetam was established using NONMEM, according to a one-compartment model with first-order absorption and elimination. To validate the model, the mean prediction error (MPE), mean squared prediction error (MSPE), root mean-squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were calculated.

Results:

A regression equation of the basic model of levetiracetam was obtained, with clearance (CL/F)=0.988 L/h, volume of distribution (V/F)=12.3 L, and K_a=1.95 h⁻¹. The final model was as follows: K_a=1.56 h⁻¹, V/F=12.1 (L), CL/F=1.04×(WEIG/25)^0.583 (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95%CI were 9.834 (−0.587–197.720), 50.919 (0.012–1286.429), 1.680 (0.021–34.184), and 0.0621 (−1.100–1.980). For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were 0.199 (−0.369–0.563), 0.002082 (0.00001–0.01054), 0.0293 (0.001−0.110), and 0.153 (−0.030–1.950).

Conclusion:

A one-compartment model with first-order absorption adequately described the levetiracetam concentrations. Body weight was identified as a significant covariate for levetiracetam clearance in this study. This model will be valuable to facilitate individualized dosage regimens.     

The withdrawal of antiepileptic drugs in patients with non-epileptic seizures: safety considerations

The majority of patients with psychogenic non-epileptic seizures (PNES) do not have epilepsy. There are a number of compelling reasons to take these patients off antiepileptic drugs (AEDs), including drug toxicity and teratogenicity, as well as possibly poorer outcome of PNES and increased risk of iatrogenic harm when patients present to emergency rooms on AEDs as emergencies. However, many patients with PNES who do not have epilepsy remain on AEDs postdiagnosis. Some studies do report patients taken off medication as an outcome measure, but with no assessment of the safety of withdrawal, or specification of the criteria for ‘excluding’ epilepsy. One study has assessed the safety of taking patients satisfying some simple criteria for the absence of an underlying epilepsy off AEDs, and has found the procedure to be safe, given appropriate postwithdrawal follow-up. Patients with PNES who do not have evidence of epilepsy should be referred to a centre with appropriate expertise in epilepsy diagnosis so that AEDs can be withdrawn in safe conditions.     

The preclinical discovery and development of brivaracetam for the treatment of focal epilepsy

Introduction: Brivaracetam (BRV) is a new AED currently licensed for the adjunctive treatment of adult patients with focal epilepsies. It is a ligand of the ubiquitous synaptic vesicle glycoprotein 2A (SV2A).

Areas covered: This paper covers the preclinical and subsequent clinical development of BRV focusing on the discovery of the SV2A protein as the main target for levetiracetam (LEV) and the main similarities and differences between LEV and BRV in terms of pharmacodynamic and pharmacokinetic properties. Phase II and Phase III studies are also presented and data from post-marketing phase IV studies are discussed.

Expert opinion: The preclinical development of BRV is quite unique and has raised several doubts on current methodologies adopted for AED development, reinforcing the need for new approaches. The preclinical and clinical profile suggest that BRV is potentially an ideal compound in the emergency setting given the rapid onset of action associated with being water soluble and, therefore, available in intravenous formulation. In addition, data from Phase III studies have already suggested that BRV may be effective not only in focal epilepsies but also in generalised syndromes. Further data from special populations such as children and women of child bearing age are urgently needed.     

拉莫三嗪联合左乙拉西坦治疗小儿难治性癫痫的临床研究

目的 探讨拉莫三嗪与左乙拉西坦联合治疗小儿难治性癫痫的疗效及对患儿血清高迁移率族蛋白1（HMGB1）、神经节苷脂抗体（GM1-A）的影响。方法 回顾性选择2017年6月—2020年6月在昆明市儿童医院治疗的难治性癫痫患儿120例为研究对象,根据患儿的治疗方案分为对照组和试验组。对照组给予左乙拉西坦片治疗,初始剂量为10～20 mg·kg^-1·d^-1,每周增加5～10 mg·kg^-1·d^-1,增加剂量至20～40 mg·kg^-1·d^-1,加量期3～7周,连续治疗6个月。试验组在对照组基础上给予拉莫三嗪片治疗,初始剂量为0.3～0.6 mg·kg^-1·d^-1,12 h服药1次,每周加量0.3～0.6 mg·kg^-1·d^-1,目标剂量5～10 mg·kg^-1·d^-1,治疗6个月。观察两组患者的治疗效果,比较治疗前及治疗6个月后两组患儿认知功能、血清炎症因子水平、血清免疫球蛋白水平、血清HMGB1、GM1-A、神经元特异性烯醇化酶（NSE）、神经肽Y（NPY）水平。记录治疗期间患儿不良反应发生情况。结果 试验组总有效率（88.33%）显著高于对照组总有效率（70%）,两组比较差异有统计学意义（P<0.05）;治疗前两组患儿的言语智商、操作智商评分比较差异无统计学意义（P>0.05）,治疗后两组患儿的言语智商、操作智商评分均显著升高（P<0.05）,且试验组升高更显著（P<0.05）;治疗前两组患儿的免疫球蛋白A（IgA）、免疫球蛋白M（IgM）、免疫球蛋白G（IgG）水平比较差异无统计学意义（P>0.05）,治疗后两组患者的IgA、IgM、IgG水平均显著升高（P<0.05）,且试验组升高更显著（P<0.05）;治疗前两组患儿的GM1-A、NSE、NPY水平比较差异无统计学意义（P>0.05）,治疗后两组患儿的GM1-A、NSE水平均显著下降（P<0.05）,NPY水平均显著升高（P<0.05）,且试验组改善更显著（P<0.05）;治疗前两组患儿的HMGB-1、肿瘤坏死因子-α（TNF-α）、超敏C反应蛋白（hs-CRP）、白细胞介素-6（IL-6）水平比较差异无统计学意义（P>0.05）,治疗后两组患儿的HMGB-1、TNF-α、hs-CRP、IL-6水平均显著下降（P<0.05）,且试验组下降更显著（P<0.05）;两组患儿的不良反应发生率比较,差异无统计学意义（P>0.05）。结论 拉莫三嗪联合左乙拉西坦治疗难治性癫痫的治疗效果较好,可改善患儿的认知功能和免疫功能,降低炎症反应,改善HMGB-1、GM1-A水平,并且安全性较好。     

The safety of rapid infusion levetiracetam: A systematic review

Epilepsy is a common diagnosis and can quickly progress to status epilepticus which requires rapid treatment. Levetiracetam is a frequent treatment choice in these situations. The approved administration of intravenous levetiracetam is an infusion over 15 min. In recent years, studies have been published on faster infusion rates of levetiracetam. The objective of this review is to discuss the safety of levetiracetam as an intravenous push at a rate quicker than recommended. A literature search using PubMed, Cochrane Library, ClinicalTrials.gov , and Google Scholar resulted in 192 articles. Inclusion criteria consisted of English language, human studies, use of levetiracetam administered intravenously at a rate faster than 15 min, discussion of safety, and full-text availability. After screening, nine articles remained for inclusion. Of the nine articles, one was a prospective, open-label study, six were retrospective studies, and two were open-label, randomized controlled trials. The most common rapid infusion speed was 5 min and doses ranged from 280 to 4500 mg. Some of these trials used undiluted levetiracetam and many reported that peripheral access was used for a portion or all of the administrations. There were few adverse effects, including specific adverse effects relating to medication concentration and speed of infusion, in all the studies. Administration of intravenous levetiracetam at a rate faster than recommended in the labeling information appears to be safe and tolerable and can be given via a peripheral line. Rapid infusion of levetiracetam is a beneficial method of administration in an acute care setting where patients need rapid attainment of therapeutic levels of antiepileptic medications. Additional research is needed to ensure that rapid administration of intravenous levetiracetam is as efficacious as the traditional dosing method.     

左乙拉西坦对海人酸致痫大鼠血清NSE和MBP变化的影响

目的:建立海人酸(KA)致痫大鼠模型并观察癫痫大鼠血清神经元特异性烯醇酶(NSE)和髓鞘碱性蛋白(MBP)的变化及左乙拉西坦(LEV)对其水平的影响,以探讨左乙拉西坦在癫痫脑损伤中是否具有保护的作用。方法:清结级Wistar雄性4~5周龄幼鼠72只,随机分为对照组24只,立体定向右侧海马注射生理盐水,KA组24只,注射海人酸,LEV治疗组24只,注射KA造模成功前12h胃管内注入LEV200mg/kg,以后未处死大鼠均每日给药一次。分别于致痫后6h、24h、72h处死,采用ELISA法检测各组大鼠血清NSE和MBP含量。结果:(1)大鼠癫痫行为;对照组无大鼠癫痫发作,其余组均有行为学改变。LEV组幼鼠癫痫发作程度与KA组类似,但潜伏期较KA组延长。(2)血清NSE变化:KA组和LEV组血清NSE于在致痫后6h升高,24h达高峰,与对照组相比有差异(P<0.05),LEV组与KA组的NSE比较无显著差异(P>0.05)。(3)MBP变化:KA组和LEV组血清MBP于致痫后6h升高,72h达高峰,与对照组相比差异有统计学意义(P<0.05),LEV组与KA组的MBP比较无显著差异(P>0.05)。结论:KA致痫大鼠血清NSE、MBP水平显著增高,提示癫痫发作可造成一过性脑损伤,血清NSE、MBP可能作为判断癫痫脑损伤程度的敏感指标,LEV对KA致痫大鼠血清NSE、MBP水平无影响,提示LEV不能减轻亦不加重癫痫发作引起的脑损伤。