中国药学杂志

Characteristic	Results
Age/years	7.25±3.99
Gender(Male/Female)	56/39
Body mass index/kg·m^-2	17.81±3.52
Medication time/years	0.48±0.39
Type of seizure,n(%)
Generalized onset	17(17.89)
Focal onset	49(51.58)
Combined generalized and focal onset	18(18.95)
Unknown onset	11(11.58)
Abnormal EEG,n(%)	67(70.53)
Dose/mg·kg^-1·d^-1	0.19±0.09
Plasma concentration/μg·mL^-1	0.47±0.36
Ratio of concentration-to-dose/μg·mL^-1·g^-1·d	2.94±2.66
Concomitant,n(%)
Monotherapy	3(3.16)
Combined with one antiseizure medication	25(26.32)
Combined with two antiseizure medication	41(43.16)
Combined with three antiseizure medication	26(27.37)
Efficacy,n(%)
Control	37(38.95)
Effective	19(20.00)
Improve	33(34.74)
Void	6(6.32)
Safety,n(%)
Somnolence	27(28.42)
Dizziness	17(17.89)
Psychiatric(Depression/Irritability)	8(8.42)
Weak	4(4.21)
Gastrointestinal reactions	5(5.26)

Characteristic	Results
Age/years	7.25±3.99
Gender(Male/Female)	56/39
Body mass index/kg·m^-2	17.81±3.52
Medication time/years	0.48±0.39
Type of seizure,n(%)
Generalized onset	17(17.89)
Focal onset	49(51.58)
Combined generalized and focal onset	18(18.95)
Unknown onset	11(11.58)
Abnormal EEG,n(%)	67(70.53)
Dose/mg·kg^-1·d^-1	0.19±0.09
Plasma concentration/μg·mL^-1	0.47±0.36
Ratio of concentration-to-dose/μg·mL^-1·g^-1·d	2.94±2.66
Concomitant,n(%)
Monotherapy	3(3.16)
Combined with one antiseizure medication	25(26.32)
Combined with two antiseizure medication	41(43.16)
Combined with three antiseizure medication	26(27.37)
Efficacy,n(%)
Control	37(38.95)
Effective	19(20.00)
Improve	33(34.74)
Void	6(6.32)
Safety,n(%)
Somnolence	27(28.42)
Dizziness	17(17.89)
Psychiatric(Depression/Irritability)	8(8.42)
Weak	4(4.21)
Gastrointestinal reactions	5(5.26)

Age /years	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration- to-dose/μg·mL^-1· g^-1·d
3<Age≤6	56	0.21±0.10	0.47±0.31	2.57±1.89
6<Age≤14	31	0.16±0.07	0.46±0.49	3.33±3.75
14<Age≤18	8	0.15±0.06	0.52±0.18	4.12±2.20
F		3.574	0.084	1.678
P		0.062	0.920	0.193

Age /years	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration- to-dose/μg·mL^-1· g^-1·d
3<Age≤6	56	0.21±0.10	0.47±0.31	2.57±1.89
6<Age≤14	31	0.16±0.07	0.46±0.49	3.33±3.75
14<Age≤18	8	0.15±0.06	0.52±0.18	4.12±2.20
F		3.574	0.084	1.678
P		0.062	0.920	0.193

Gender	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration- to-dose/μg·mL^-1· g^-1·d
Male	56	0.19±0.08	0.47±0.30	2.84±2.05
Female	39	0.19±0.11	0.48±0.45	3.09±3.37
t		-0.256	-0.120	-0.427
P		0.799	0.905	0.671

Gender	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration- to-dose/μg·mL^-1· g^-1·d
Male	56	0.19±0.08	0.47±0.30	2.84±2.05
Female	39	0.19±0.11	0.48±0.45	3.09±3.37
t		-0.256	-0.120	-0.427
P		0.799	0.905	0.671

BMI	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration-to-dose /μg·mL^-1·g^-1·d	t	P	Effective (n,%)	χ²	P
BMI<18.5	60	0.21±0.09	0.44±0.29	2.46±1.87	-	-	39,65.00%	-	-
18.5≤BMI<24.0	32	0.17±0.07	0.54±0.48	3.66±3.64 ¹⁾	1.207	0.037¹⁾	15,46.88%	6.57	0.010¹⁾
BMI≥24.0	3	0.09±0.02	0.44±0.08	4.99±1.43 ¹⁾	2.540	0.102	1,33.33%	20.49	<0.01¹⁾

BMI	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration-to-dose /μg·mL^-1·g^-1·d	t	P	Effective (n,%)	χ²	P
BMI<18.5	60	0.21±0.09	0.44±0.29	2.46±1.87	-	-	39,65.00%	-	-
18.5≤BMI<24.0	32	0.17±0.07	0.54±0.48	3.66±3.64 ¹⁾	1.207	0.037¹⁾	15,46.88%	6.57	0.010¹⁾
BMI≥24.0	3	0.09±0.02	0.44±0.08	4.99±1.43 ¹⁾	2.540	0.102	1,33.33%	20.49	<0.01¹⁾

Concomitant	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration-to-dose /μg·mL^-1·g^-1·d	F	P
Combined cytochrome P450 enzyme inducer	50	0.21±0.10	0.50±0.43	2.73±3.06	0.662	0.518
Combined sodium channel blockers	74	0.19±0.10	0.50±0.39	3.11±2.87	0.274	0.761
Monotherapy	14	0.19±0.07	0.42±0.25	2.59±1.87	0.364	0.696

Concomitant	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration-to-dose /μg·mL^-1·g^-1·d	F	P
Combined cytochrome P450 enzyme inducer	50	0.21±0.10	0.50±0.43	2.73±3.06	0.662	0.518
Combined sodium channel blockers	74	0.19±0.10	0.50±0.39	3.11±2.87	0.274	0.761
Monotherapy	14	0.19±0.07	0.42±0.25	2.59±1.87	0.364	0.696

新型抗癫痫药物吡仑帕奈在新疆癫痫患儿中的血药浓度测定及影响因素分析

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赵婷 ^1a^,^1b , 张惠兰 ^1a^,^1b , 冯继荣 ² , 于静 ² , 于鲁海 ^1a^,^1b , 冯杰 ^1a^,^1b , 王婷婷 ^1a^,^1b , 孙岩 ² , 李红健 ^1a^,^1b^,^*

中国药学杂志 | 论著 2024,59(13): 1233-1237

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中国药学杂志 | 论著 2024, 59(13): 1233-1237

新型抗癫痫药物吡仑帕奈在新疆癫痫患儿中的血药浓度测定及影响因素分析

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赵婷^1a^,^1b, 张惠兰^1a^,^1b, 冯继荣², 于静², 于鲁海^1a^,^1b, 冯杰^1a^,^1b, 王婷婷^1a^,^1b, 孙岩², 李红健^1a^,^1b^,^*

作者信息

¹ 新疆维吾尔自治区人民医院, a.药学部; b.临床药学研究所, 乌鲁木齐 830000

² 新疆维吾尔自治区儿童医院(北京儿童医院新疆医院)神经内科, 乌鲁木齐 830000

赵婷,女,硕士,主管药师研究方向:抗癫痫药物的个体化治疗

通讯作者:

* 李红健,男,硕士,主任药师研究方向:儿科临床药学 Tel:(0991)8562413

Determination of Plasma Concentration and Influencing Factors of A New Antiepileptic Drug, Perampanel, in Children with Epilepsy in Xinjiang

Ting ZHAO^1a^,^1b, Huilan ZHANG^1a^,^1b, Jirong FENG², Jing YU², Luhai YU^1a^,^1b, Jie FENG^1a^,^1b, Tingting WANG^1a^,^1b, Yan SUN², Hongjian LI^1a^,^1b^,^*

Affiliations

¹ a. Department of Pharmacy, 1b. Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830000, China

² Department of Pediatrics, Children's Hospital of Xinjiang Uygur Autonomous Region (Xinjiang Hospital of Beijing Pediatric patients's Hospital), Urumqi 830000, China

出版时间: 2024-07-08 doi: 10.11669/cpj.2024.13.008

文章导航

摘要

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目的吡仑帕奈(perampanel,PER)于2019年在我国批准上市,笔者未见与PER血药浓度监测相关的研究报道。本研究旨在探讨癫痫患儿的年龄、性别、体重指数、癫痫类型、给药剂量和合并用药对PER稳态血药浓度的影响。方法收集2019年—2023年就诊于新疆维吾尔自治区人民医院和新疆维吾尔自治区儿童医院并规律服用PER的4~14岁癫痫患儿的血清样本95例,用超高效液相色谱法进行血药浓度测定,并分析患儿年龄、性别、身体质量指数(BMI)、给药剂量及合并用药等因素对其血药浓度的影响。结果患儿年龄分布为4.25~14岁,平均(7.25±3.99)岁;PER的血药浓度0.13~0.99 μg·mL^-1,平均(0.47±0.36)μg·mL^-1。不同年龄组、性别组患儿的PER血药浓度和浓度剂量比(ratio of concentration dose,CDR)结果均无显著性差异(P>0.05)。18.5≤BMI<24.0患儿的CDR结果显著高于BMI<18.5组患儿,差异均具有统计学意义(t=-1.207,P<0.05)。合并用药对PER的给药剂量、血药浓度和CDR结果均无显著影响(P>0.05)。PER血药浓度与给药剂量的相关性较差(r=0.113)。结论患儿临床应用PER治疗癫痫的过程中有必要进行治疗药物监测,使PER血药浓度控制在治疗剂量范围内而提高临床疗效并减少不良反应发生率。

关键词

癫痫 / 吡仑帕奈 / 血药浓度

Abstract

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OBJECTIVE To investigate the effects of age, gender, body mass index (BMI), type of epilepsy, dosage and combined medication on the steady-state serum concentration of perampanel in children with epilepsy. METHODS A total of 95 serum samples from 4 to 14 years old children with epilepsy who were admitted to our hospital from 2019 to 2023 and took perampanel regularly were collected. The serum concentration was determined by high performance liquid chromatography. The influence of factors such as gender, BMI, dosage and combined medication on the concentration were analyzed. RESULTS The children aged 4.25-14 (7.25±3.99) years. The serum concentration of perampanel was 0.13-0.99(0.47±0.36)μg·mL^-1. There were no significant differences in the serum concentration and ratio of concentration dose (CDR) of perampanel among different age groups and gender groups (P>0.05). The CDRs of patients of 18.5≤BMI<24.0 group were significantly higher than those of BMI<18.5 group (t=-1.207, P<0.05). The combination of drug had no significant effects on the dosage, blood concentration and CDR of perampanel (P>0.05). The correlation between perampanel concentration and dose was poor (r=0.113). CONCLUSION In the course of using perampanel for the treatment of epilepsy in children, it is necessary to conduct therapeutic drug monitoring, so that the concentration can be controlled within the therapeutic range to ensure clinical efficacy and reduce the incidence of adverse reactions.

Key words

epilepsy / perampanel / plasma concentration

引用本文

赵婷, 张惠兰, 冯继荣, 于静, 于鲁海, 冯杰, 王婷婷, 孙岩, 李红健. 新型抗癫痫药物吡仑帕奈在新疆癫痫患儿中的血药浓度测定及影响因素分析. 中国药学杂志, 2024 , 59 (13) : 1233 -1237 . DOI: 10.11669/cpj.2024.13.008

Ting ZHAO, Huilan ZHANG, Jirong FENG, Jing YU, Luhai YU, Jie FENG, Tingting WANG, Yan SUN, Hongjian LI. Determination of Plasma Concentration and Influencing Factors of A New Antiepileptic Drug, Perampanel, in Children with Epilepsy in Xinjiang[J]. Chinese Pharmaceutical Journal, 2024 , 59 (13) : 1233 -1237 . DOI: 10.11669/cpj.2024.13.008

正文

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吡仑帕奈(perampanel,PER)是由卫材制药开发的世界首个非竞争性α-氨基-3-羟基-5-甲基异噁唑-4-丙酸(AMPA)受体拮抗药,欧洲EMA和美国FDA批准用于治疗≥4岁患者的部分性癫痫发作^[1-2]。我国于2019年批准PER上市,但目前国内尚无与PER血药浓度监测相关的研究报道。临床研究表明,PER具有良好的短期和长期疗效和耐受性^[3-7]。PER口服生物利用度较高,半衰期较长(53~136 h),推荐每天给药1次,由肝脏CYP3A4代谢^[8]。本研究测定了95例新疆癫痫患儿的PER稳态血药浓度,并探讨年龄、性别、体重指数及合并用药对患儿PER血药浓度的影响,旨在为PER在我院的临床合理用药提供参考。

1 资料和方法

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1.1 研究对象

收集2020年—2023年期间在新疆维吾尔自治区人民医院和新疆维吾尔自治区儿童医院接受PER治疗的癫痫患儿95例。入选标准:符合国际抗癫痫联盟最新的癫痫发作类型及癫痫诊断^[9];3~14周岁;经PER治疗并监测PER血药浓度者。排除标准:采集血样时间点不明确者;研究资料缺失者;接受透析或利尿等显著影响药物消除者。

本研究得到新疆维吾尔自治区人民医院伦理委员会批准(批准号:KY2022120614)。参与本研究的患儿监护人均签署知情同意书。在签署表格之前,所有患者和他们的父母都被告知发表研究结果的可能性。加入前数据完全匿名。

1.2 仪器、试剂和试药

PER对照品(纯度98.00%,批号380917-97-5,Sigma-Aldrich公司);同位素内标(ER-167615,日本Eisai公司);甲醇、甲酸均为质谱级。健康献血者的空白人血清样本由新疆维吾尔自治区人民医院体检中心在征得每位受试者书面同意后友好提供。

1.3 血药浓度检测^[10]

色谱柱:Waters ACQUITY UPLC BEH C₁₈柱(2.1 mm×100 mm,1.7 μm),流动相:乙腈-1‰甲酸水溶液(40:60),流速 0.15 mL·min^-1,进样量8 μL,检测波长 320 nm,柱温30 ℃。

精密吸取血浆样品90 μL,加入内标溶液10 μL,涡旋混合60 s,精密加入蛋白沉淀剂200 μL,涡旋混合90 s,13 400 r·min^-1离心10 min,用注射器吸取上清液,经0.22 μm 针头式过滤器过滤后进样测定,记录色谱图,采用内标法进行定量分析。

方法学考察:PER和内标溶液的保留时间分别为6.4和2.6 min。定量样品上限(200 ng·mL^-1)后,空白血浆样品在色谱中未检出残留。PER在0.100~3.200 μg·mL^-1内与峰面积Y的线性关系良好(Y=0.109 9X+0.002 3,r=0.999),检测下限为0.5 ng·mL^-1(S/N=4),定量下限为5 ng·mL^-1(S/N=12)。定量下限(LLOQ)、低浓度质控(LQC)、中浓度质控(MQC)和高浓度质控(HQC) 的日内和日间精密度的相对标准偏差(RSD)值均<5.00%,准确度在理论浓度的±15.00% 内,提取回收率为 98.65%~101.18%,RSD 值均<5.00%,室温、短期、长期和冻融冻存稳定性均较好(RSD<10.00%)。

1.4 样本采集及临床资料收集

所有患儿均遵医嘱规律服用PER片治疗至少2周,并达到稳态血药浓度后空腹抽取静脉血2~3 mL,4 500 r·min^-1的转速低温离心5 min,按“1.3”项下方法处理,测定PER稳态血药浓度。同时,查阅患儿相关临床资料(如年龄、性别、身高、体重、给药时长、给药剂量、脑电图、合并其他ASMs的数量和类型等)。

苯妥英钠、卡马西平、奥卡西平和拉莫三嗪被归类为细胞色素P450酶诱导剂。丙戊酸钠、左乙拉西坦和托吡酯被归类为钠通道阻滞剂(sodium channel blockers,SCBs)。根据患儿的合并用药情况,将其分为以下3组,第1组:PER合并细胞色素P450酶诱导剂组;第2组:PER合并SCBs组;第3组:PER单药或其他药物组。

1.5 统计学分析

使用SPSS版本19.0软件(版本:4.0.100.1124)进行分析,P<0.05被认为具有统计学意义。临床资料呈现采用描述性统计。定量变量采用t检验或方差分析。所有计量资料均以$\bar{x}±s$表示。采用二元Logistic回归分析影响血浆PER浓度的因素。用Person chi-square test进行相关性分析。

2 结果

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2.1 一般资料

95例癫痫患儿的基本资料见表1。患儿年龄分布为4.25~14岁,平均(7.25±3.99)岁;体质量12.93~28.96 kg·m^-2,平均体质量是(17.81±3.52)kg·m^-2;经体质量校正的PER给药剂量为0.05~0.38 mg·kg^-1·d^-1,平均(0.26±0.68)mg·kg^-1·d^-1;PER的血药浓度为0.13~0.99 μg·mL^-1,平均(0.47±0.36)μg·mL^-1。PER的治疗癫痫有效率为58.95%。在使用初期,发生的不良反应多为头晕和嗜睡,且均为一过性,无因不良反应导致停药的病例。

2.2 年龄因素对PER稳态血药浓度的影响

根据儿科学小儿学龄分期可得知,3周岁以下为婴幼儿,3~6周岁为学龄期儿童,6~14周岁为青春期儿童^[11]。本研究纳入的患儿年龄均大于3周岁,故将癫痫患儿根据年龄进行分组,其中3岁<年龄≤6岁的患儿56例,6岁<年龄≤14岁的患儿31例,14岁<年龄≤18岁的患儿8例,不同年龄组患儿PER给药剂量、血药浓度及浓度剂量比(Ratio of concentration dose,CDR)结果见表2。方差分析结果显示:不同年龄组患儿的PER血药浓度和CDR结果均无显著性差异(P>0.05)。

2.3 性别因素对PER稳态血药浓度的影响

本研究纳入男性患儿56例,女性患39例。不同性别组患儿的PER给药剂量、稳态血药浓度及CDR结果见表3。方差分析结果显示:PER的给药剂量、血药浓度和CDR结果在男女性别之间的差异无统计学意义(P>0.05)。

2.4 体质量指数对PER稳态血药浓度和临床疗效的影响

根据患儿根据体质量指数(body mass index,BMI)将其分为3组,其中BMI<18.5的患儿60例,18.5≤BMI<24.0的患儿32例,BMI≥24.0的患儿3例,不同BMI组患儿PER给药剂量、血药浓度、CDR结果和临床疗效见表4。方差分析结果显示:18.5≤BMI<24.0患儿的CDR结果显著高于BMI<18.5组患儿,差异均具有统计学意义(t=-1.207,P<0.05)。卡方分析结果显示:18.5≤BMI<24.0和BMI≥24.0患儿的治疗有效率显著低于BMI < 18.5组患儿,差异均具有统计学意义(P<0.05)。

2.5 合并用药对PER血药浓度的影响

PER合并细胞色素P450酶诱导剂组患儿50例;PER合并SCBs组患儿74例。方差分析结果显示:PER的给药剂量、血药浓度和CDR结果在不同合并用药组之间的差异无统计学意义(P>0.05)(表5)。

2.6 相关性分析

PER血药浓度(ρ)与给药剂量(x)的相关性较差,线性回归方程为ρ=0.445x+3.881(r=0.113),见图1。

2.7 PER血药浓度与临床疗效的相关性评价

以患儿临床疗效为因变量,PER血药浓度(C_ss)为自变量,进行Logistic回归分析。分析结果表明,PER临床疗效与血药浓度有较好的相关性[Logistic(P)=0.696C_ss-0.362,OR(95%CI)=1.363(0.443~4.194),P<0.01]。患儿PER稳态血药浓度对于疗效的预判准确性[诊断曲线下面积为AUC(95%CI)=0.663(0.441~0.685)]高于给药剂量[AUC(95%CI)=0.543(0.419~0.668)],结果见图2。

3 讨论

收起

自PER应用于患者抗癫痫治疗以来,许多临床研究均证实了PER对癫痫的有效性和耐受性^[12-14]。目前国内尚无癫痫患儿PER血药浓度测定相关的研究报道,临床亦缺乏适合中国儿童的药物治疗参数。本研究是PER于2019年在我国上市后进行的。

随着越来越多的研究证实抗癫痫药物的血药浓度与临床疗效和安全性密切相关,抗癫痫药物的治疗药物监测(therapeutic drug monitoring,TDM)在临床上的应用也越来越广泛^[15-16]。因此,确定癫痫患儿抗癫痫血浆药物浓度的最佳范围是至关重要的,这能保证其安全性。各种相关因素,如年龄、性别、体重、身高、种族、饮食和合并用药等,均可能影响抗癫痫药物血药浓度和疗效。因此,本研究首次在新疆癫痫患儿中探讨癫痫患儿的年龄、性别、体重指数、癫痫类型、给药剂量和合并用药对PER稳态血药浓度的影响。这项研究是在PER引入中国的前3年进行的,当时大多数医生开始获得这种新的ASM的经验。

本研究结果发现,PER血浆药物浓度与年龄、性别无关,但与BMI相关。18.5≤BMI<24.0患儿的PER血药浓度显著高于BMI < 18.5组患儿。因此,临床药师应及时做好PER的用药指导,尤其是BMI<18.5的患儿,如选择适宜的药物剂型及给药途径、严格掌握用药的剂量、同时定期监测患儿的血药浓度结果,并根据血药浓度结果及时调整给药剂量等。

多项临床研究表明,PER具有较高的口服生物利用度、剂量和浓度呈线性关系,以及药物-药物相互作用较小^[15,17-19]。Yamamoto等 ^[15]报道PER血药浓度与剂量呈线性关系,同时使用酶诱导剂可导致PER血药浓度显著降低。然而,Contin等 ^[17]报道PER血浆浓度-剂量关系相关性较弱(r=0.390)。本研究结果显示PER血药浓度与给药剂量的相关性较差(r=0.113),与Contin等^[17]的研究结果相一致。这一结果可能考虑与患儿BMI较低,依从性较差,并合并各种抗癫痫药物,特别细胞色素P450酶诱导剂相关。

综上所述,PER可能不需要在所有患者中进行常规血药浓度监测,有条件的机构可根据自身的临床与科研需求决定是否进行血药浓度监测。然而,对于BMI<18.5的患儿,以及服用PER的同时合并细胞色素P450酶诱导剂或SCBs的患者,其血药浓度监测更具有其必要性。

因此癫痫患儿在PER用药过程中有必要进行其药物监测,并深入研究适合于新疆儿童群体的血药浓度参考范围,以便及时调整给药剂量,使儿童PER血药浓度控制在治疗剂量范围内而提高临床疗效并减少不良反应的发生率。

基金

收起

中国抗癫痫协会AMPA机制及抗癫痫药物研究科研基金(CW-202-016)

参考文献

收起

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收起

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2024年第59卷第13期

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文章信息

doi: 10.11669/cpj.2024.13.008

接收时间：2023-04-03
首发时间：2026-01-14
出版时间：2024-07-08

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收稿日期：2023-04-03

基金

中国抗癫痫协会AMPA机制及抗癫痫药物研究科研基金(CW-202-016)

作者信息

¹ 新疆维吾尔自治区人民医院, a.药学部; b.临床药学研究所, 乌鲁木齐 830000

² 新疆维吾尔自治区儿童医院(北京儿童医院新疆医院)神经内科, 乌鲁木齐 830000

通讯作者:

* 李红健,男,硕士,主任药师研究方向:儿科临床药学 Tel:(0991)8562413

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Characteristic	Results
Age/years	7.25±3.99
Gender(Male/Female)	56/39
Body mass index/kg·m^-2	17.81±3.52
Medication time/years	0.48±0.39
Type of seizure,n(%)
Generalized onset	17(17.89)
Focal onset	49(51.58)
Combined generalized and focal onset	18(18.95)
Unknown onset	11(11.58)
Abnormal EEG,n(%)	67(70.53)
Dose/mg·kg^-1·d^-1	0.19±0.09
Plasma concentration/μg·mL^-1	0.47±0.36
Ratio of concentration-to-dose/μg·mL^-1·g^-1·d	2.94±2.66
Concomitant,n(%)
Monotherapy	3(3.16)
Combined with one antiseizure medication	25(26.32)
Combined with two antiseizure medication	41(43.16)
Combined with three antiseizure medication	26(27.37)
Efficacy,n(%)
Control	37(38.95)
Effective	19(20.00)
Improve	33(34.74)
Void	6(6.32)
Safety,n(%)
Somnolence	27(28.42)
Dizziness	17(17.89)
Psychiatric(Depression/Irritability)	8(8.42)
Weak	4(4.21)
Gastrointestinal reactions	5(5.26)

Characteristic

Results

Age/years

7.25±3.99

Gender(Male/Female)

56/39

Body mass index/kg·m^-2

17.81±3.52

Medication time/years

0.48±0.39

Type of seizure,n(%)

Generalized onset

17(17.89)

Focal onset

49(51.58)

Combined generalized and focal onset

18(18.95)

Unknown onset

11(11.58)

Abnormal EEG,n(%)

67(70.53)

Dose/mg·kg^-1·d^-1

0.19±0.09

Plasma concentration/μg·mL^-1

0.47±0.36

Ratio of concentration-to-dose/μg·mL^-1·g^-1·d

2.94±2.66

Concomitant,n(%)

Monotherapy

3(3.16)

Combined with one antiseizure medication

25(26.32)

Combined with two antiseizure medication

41(43.16)

Combined with three antiseizure medication

26(27.37)

Efficacy,n(%)

Control

37(38.95)

Effective

19(20.00)

Improve

33(34.74)

Void

6(6.32)

Safety,n(%)

Somnolence

27(28.42)

Dizziness

17(17.89)

Psychiatric(Depression/Irritability)

8(8.42)

Weak

4(4.21)

Gastrointestinal reactions

5(5.26)

Age /years	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration- to-dose/μg·mL^-1· g^-1·d
3<Age≤6	56	0.21±0.10	0.47±0.31	2.57±1.89
6<Age≤14	31	0.16±0.07	0.46±0.49	3.33±3.75
14<Age≤18	8	0.15±0.06	0.52±0.18	4.12±2.20
F		3.574	0.084	1.678
P		0.062	0.920	0.193

Age
/years

Dose
/mg·kg^-1·d^-1

Plasma
concentration
/μg·mL^-1

Ratio of concentration-
to-dose/μg·mL^-1·
g^-1·d

3<Age≤6

0.21±0.10

0.47±0.31

2.57±1.89

6<Age≤14

0.16±0.07

0.46±0.49

3.33±3.75

14<Age≤18

0.15±0.06

0.52±0.18

4.12±2.20

3.574

0.084

1.678

0.062

0.920

0.193

Gender	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration- to-dose/μg·mL^-1· g^-1·d
Male	56	0.19±0.08	0.47±0.30	2.84±2.05
Female	39	0.19±0.11	0.48±0.45	3.09±3.37
t		-0.256	-0.120	-0.427
P		0.799	0.905	0.671

Gender

Dose
/mg·kg^-1·d^-1

Plasma
concentration
/μg·mL^-1

Ratio of concentration-
to-dose/μg·mL^-1·
g^-1·d

Male

0.19±0.08

0.47±0.30

2.84±2.05

Female

0.19±0.11

0.48±0.45

3.09±3.37

-0.256

-0.120

-0.427

0.799

0.905

0.671

BMI	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration-to-dose /μg·mL^-1·g^-1·d	t	P	Effective (n,%)	χ²	P
BMI<18.5	60	0.21±0.09	0.44±0.29	2.46±1.87	-	-	39,65.00%	-	-
18.5≤BMI<24.0	32	0.17±0.07	0.54±0.48	3.66±3.64 ¹⁾	1.207	0.037¹⁾	15,46.88%	6.57	0.010¹⁾
BMI≥24.0	3	0.09±0.02	0.44±0.08	4.99±1.43 ¹⁾	2.540	0.102	1,33.33%	20.49	<0.01¹⁾

BMI

Dose
/mg·kg^-1·d^-1

Plasma concentration
/μg·mL^-1

Ratio of concentration-to-dose
/μg·mL^-1·g^-1·d

Effective
(n,%)

χ²

BMI<18.5

0.21±0.09

0.44±0.29

2.46±1.87

39,65.00%

18.5≤BMI<24.0

0.17±0.07

0.54±0.48

3.66±3.64 ¹⁾

1.207

0.037¹⁾

15,46.88%

6.57

0.010¹⁾

BMI≥24.0

0.09±0.02

0.44±0.08

4.99±1.43 ¹⁾

2.540

0.102

1,33.33%

20.49

<0.01¹⁾

Concomitant	n	Dose /mg·kg^-1·d^-1	Plasma concentration /μg·mL^-1	Ratio of concentration-to-dose /μg·mL^-1·g^-1·d	F	P
Combined cytochrome P450 enzyme inducer	50	0.21±0.10	0.50±0.43	2.73±3.06	0.662	0.518
Combined sodium channel blockers	74	0.19±0.10	0.50±0.39	3.11±2.87	0.274	0.761
Monotherapy	14	0.19±0.07	0.42±0.25	2.59±1.87	0.364	0.696

Concomitant

Dose
/mg·kg^-1·d^-1

Plasma concentration
/μg·mL^-1

Ratio of concentration-to-dose
/μg·mL^-1·g^-1·d

Combined cytochrome P450 enzyme inducer

0.21±0.10

0.50±0.43

2.73±3.06

0.662

0.518

Combined sodium channel blockers

0.19±0.10

0.50±0.39

3.11±2.87

0.274

0.761

Monotherapy

0.19±0.07

0.42±0.25

2.59±1.87

0.364

0.696