Influencing factors of plasma concentration of lamotrigine in the treatment of epilepsy in children: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Jingjing ^1,2,3 , HUANG Liang ^1,2,3 , ZENG Linan ^1,2,3 , JIANG Zhimei ^1,2,3 , LIU Zheng ^1,2,3,4 , JIA Zhijun ^1,2,3,5 , MIAO Liyan ⁶ ,  ZHAO Limei ⁷ , ZHANG Lingli ^1,2,3

1. Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, P. R. China;
3. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu 610041, P. R. China;
4. West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;
5. West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China;
6. The First Affiliated Hospital of Soochow University, Suzhou 215006, P. R. China;
7. Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, P. R. China;

Corresponding author：

ZHAO Limei, Email: zhanglingli@scu.edu.cn

Keywords：

Epilepsy; Lamotrigine; Children; Concentration; Influencing factor; Systematic review

DOI：

10.7507/1672-2531.202111094

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Objective To systematically review the factors influencing plasma concentration of lamotrigine (LTG) in the treatment of epilepsy in children.Methods Databases including PubMed, EMbase, The Cochrane Library, CNKI, WanFang Data, VIP and CBM were electronically searched to collect clinical studies on the factors influencing plasma concentration of LTG in the treatment of epilepsy in children from database inception to December 2020. Two researchers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. A systematic review was then performed to analyze the factors influencing plasma concentration of LTG in the treatment of epilepsy in children. Results A total of 21 studies were included. The results of systematic review suggested that dosage and some combination drugs (valproic acid, carbamazepine, phenytoin sodium, topiramate, ethosuximide, rufinamide, fluoxetine, clonazepam, clobazam and ethinylestradiol) were potential factors influencing LTG concentration. Four gene polymorphisms (UGT1A4 142T>G, UGT1A4 219C>T, UGT1A4 163G>A, and OCT1 M408V A>G), age, weight, sex, and combination drugs (phenobarbital and levetiracetam) might affect the plasma concentration of LTG in children. The effects of oxcarbazepine, 16 gene polymorphisms (UGT1A4 *3 T>G, UGT2B7 211G>T, UGT2B7 372A>G, UGT2B7 735A>G, UGT2B7 801T>A, UGT2B7 802C>T, UGT2B7 161C>T, SCN1A IVS591G>A, SCN2A c.56G>A, SCN2A c.59G>A, MDR1 1236 C>T, MDR1 2677 G>T/A, MDR1 3435 C>T, SLC22A1 1022C>T, ABCB1 3435 C>T and ABCB1 1236C>T), ketogenic diet, and ethnicity (Uygur/Han) on the plasma concentration of LTG in children were not found. Conclusion The plasma concentration of LTG in the treatment of epilepsy in children is affected by many factors, and more high-quality prospective studies should be carried out to further clarify the factors influencing the plasma concentration of LTG in children.

Citation： CHEN Jingjing, HUANG Liang, ZENG Linan, JIANG Zhimei, LIU Zheng, JIA Zhijun, MIAO Liyan, ZHAO Limei, ZHANG Lingli. Influencing factors of plasma concentration of lamotrigine in the treatment of epilepsy in children: a systematic review. Chinese Journal of Evidence-Based Medicine, 2022, 22(5): 550-557. doi: 10.7507/1672-2531.202111094 Copy

1.	中华医学会儿科学分会神经学组. 儿童癫痫长程管理专家共识. 中华儿科杂志, 2013, 51(9): 699-703.
2.	Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia, 2008, 49(7): 1239-1276.
3.	Hirsch LJ, Weintraub DB, Buchsbaum R, et al. Predictors of lamotrigine-associated rash. Epilepsia, 2006, 47(2): 318-322.
4.	联合国儿童基金会. 儿童权利公约, 1989. Available at: https://www.unicef.org/zh/%E5%84%BF%E7%AB%A5%E6%9D%83%E5%88%A9%E5%85%AC%E7%BA%A6.
5.	Hu J, Dong Y, Chen X, et al. Prevalence of suicide attempts among Chinese adolescents: a meta-analysis of cross-sectional studies. Compr Psychiatry, 2015, 61: 78-89.
6.	Ma LL, Wang YY, Yang ZH, et al. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better. Mil Med Res, 2020, 7(1): 7.
7.	Du Z, Jiao Y, Shi L. Association of UGT2B7 and UGT1A4 polymorphisms with serum concentration of antiepileptic drugs in children. Med Sci Monit, 2016, 22: 4107-4113.
8.	Wang Q, Liang M, Dong Y, et al. Effects of UGT1A4 genetic polymorphisms on serum lamotrigine concentrations in Chinese children with epilepsy. Drug Metab Pharmacokinet, 2015, 30(3): 209-213.
9.	Yamamoto Y, Takahashi Y, Imai K, et al. Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy. Drug Metab Pharmacokinet, 2015, 30(3): 214-220.
10.	Liu L, Zhao L, Wang Q, et al. Influence of valproic acid concentration and polymorphism of UGT1A43, UGT2B7 -161C > T and UGT2B72 on serum concentration of lamotrigine in Chinese epileptic children. Eur J Clin Pharmacol, 2015, 71(11): 1341-1347.
11.	Otoul C, De Smedt H, Stockis A. Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. Epilepsia, 2007, 48(11): 2111-2115.
12.	Reimers A, Skogvoll E, Sund JK, et al. Lamotrigine in children and adolescents: the impact of age on its serum concentrations and on the extent of drug interactions. Eur J Clin Pharmacol, 2007, 63(7): 687-692.
13.	Dahlin MG, Beck OM, Amark PE. Plasma levels of antiepileptic drugs in children on the ketogenic diet. Pediatr Neurol, 2006, 35(1): 6-10.
14.	Takeuchi T, Natsume J, Kidokoro H, et al. The effects of co-medications on lamotrigine clearance in Japanese children with epilepsy. Brain Dev, 2016, 38(8): 723-730.
15.	王秋宁. 代谢酶和转运体基因多态性对拉莫三嗪代谢及药物相互作用的影响. 沈阳: 中国医科大学, 2015.
16.	闫彩萍, 郝润喜. 拉莫三嗪和卡马西平联用时对儿童血药浓度的影响. 中国实用医药, 2013, 8(31): 176-177.
17.	王璐. 对影响拉莫三嗪稳态血药浓度的相关因素分析. 当代医药论丛, 2015, (4): 128-129.
18.	何艳玲, 和凡, 莫小兰, 等. 根据UGT1A4 142T>G基因多态性和丙戊酸血药浓度定量估算我国汉族癫痫儿童体内拉莫三嗪的血药浓度. 中国药房, 2017, 28(20): 2737-2742.
19.	和凡, 何艳玲, 祁俊华, 等. 合并抗癫痫药物对癫痫患儿拉莫三嗪血药浓度的影响. 儿科药学杂志, 2013, 19(9): 33-36.
20.	闫彩萍, 郝润喜. 癫痫儿童联用拉莫三嗪与丙戊酸时血药浓度观察. 山西医科大学学报, 2013, 44(12): 971-972.
21.	李丹, 黄绍平. 拉莫三嗪血药浓度与剂量合并用药和年龄关系研究. 中国实用儿科杂志, 2014, 29(10): 763-765.
22.	王威, 陈文伟, 褚燕琦, 等. 联用丙戊酸对儿童和成人癫痫患者拉莫三嗪血药浓度的影响. 临床药物治疗杂志, 2018, 16(11): 56-60.
23.	陈亚南, 徐善森, 邱枫, 等. 钠离子通道基因与转运体基因多态性对拉莫三嗪血药浓度的影响. 中国临床药理学杂志, 2016, 32(22): 2069-2072.
24.	贾莉, 周明明, 李红健, 等. 新疆地区维吾尔族, 汉族癫痫患儿拉莫三嗪血药浓度对比分析. 儿科药学杂志, 2015, 21(1): 34-36.
25.	包军, 何英, 苏渊, 等. 影响拉莫三嗪稳态血药浓度的相关因素研究. 中华儿科杂志, 2001, 39(8): 457-460.
26.	赵婷, 李红健, 王婷婷, 等. 新疆癫痫患儿拉莫三嗪稳态血药浓度影响因素的研究. 中国临床药理学杂志, 2021, 37(15): 1981-1984.
27.	楼江, 林能明, 陈玲, 等. 多个癫痫相关基因多态性与拉莫三嗪治疗儿童癫痫血药浓度的相关性. 中华全科医学, 2021, 19(1): 17-19,45.
28.	Yasam VR, Jakki SL, Senthil V, et al. A pharmacological overview of lamotrigine for the treatment of epilepsy. Expert Rev Clin Pharmacol, 2016, 9(12): 1533-1546.
29.	Weintraub D, Buchsbaum R, Resor SR, et al. Effect of antiepileptic drug comedication on lamotrigine clearance. Arch Neurol, 2005, 62(9): 1432-1436.
30.	Miyagi SJ, Collier AC. Pediatric development of glucuronidation: the ontogeny of hepatic UGT1A4. Drug Metab Dispos, 2007, 35(9): 1587-1592.
31.	李臻, 王雁. UGT1A4142T>G基因多态性与中国癫痫患者拉莫三嗪血药浓度关系的荟萃分析. 中华医学杂志, 2018, 98(41): 3365-3370.

1. 中华医学会儿科学分会神经学组. 儿童癫痫长程管理专家共识. 中华儿科杂志, 2013, 51(9): 699-703.
2. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia, 2008, 49(7): 1239-1276.
3. Hirsch LJ, Weintraub DB, Buchsbaum R, et al. Predictors of lamotrigine-associated rash. Epilepsia, 2006, 47(2): 318-322.
4. 联合国儿童基金会. 儿童权利公约, 1989. Available at: https://www.unicef.org/zh/%E5%84%BF%E7%AB%A5%E6%9D%83%E5%88%A9%E5%85%AC%E7%BA%A6.
5. Hu J, Dong Y, Chen X, et al. Prevalence of suicide attempts among Chinese adolescents: a meta-analysis of cross-sectional studies. Compr Psychiatry, 2015, 61: 78-89.
6. Ma LL, Wang YY, Yang ZH, et al. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better. Mil Med Res, 2020, 7(1): 7.
7. Du Z, Jiao Y, Shi L. Association of UGT2B7 and UGT1A4 polymorphisms with serum concentration of antiepileptic drugs in children. Med Sci Monit, 2016, 22: 4107-4113.
8. Wang Q, Liang M, Dong Y, et al. Effects of UGT1A4 genetic polymorphisms on serum lamotrigine concentrations in Chinese children with epilepsy. Drug Metab Pharmacokinet, 2015, 30(3): 209-213.
9. Yamamoto Y, Takahashi Y, Imai K, et al. Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy. Drug Metab Pharmacokinet, 2015, 30(3): 214-220.
10. Liu L, Zhao L, Wang Q, et al. Influence of valproic acid concentration and polymorphism of UGT1A4*3, UGT2B7 -161C > T and UGT2B7*2 on serum concentration of lamotrigine in Chinese epileptic children. Eur J Clin Pharmacol, 2015, 71(11): 1341-1347.
11. Otoul C, De Smedt H, Stockis A. Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. Epilepsia, 2007, 48(11): 2111-2115.
12. Reimers A, Skogvoll E, Sund JK, et al. Lamotrigine in children and adolescents: the impact of age on its serum concentrations and on the extent of drug interactions. Eur J Clin Pharmacol, 2007, 63(7): 687-692.
13. Dahlin MG, Beck OM, Amark PE. Plasma levels of antiepileptic drugs in children on the ketogenic diet. Pediatr Neurol, 2006, 35(1): 6-10.
14. Takeuchi T, Natsume J, Kidokoro H, et al. The effects of co-medications on lamotrigine clearance in Japanese children with epilepsy. Brain Dev, 2016, 38(8): 723-730.
15. 王秋宁. 代谢酶和转运体基因多态性对拉莫三嗪代谢及药物相互作用的影响. 沈阳: 中国医科大学, 2015.
16. 闫彩萍, 郝润喜. 拉莫三嗪和卡马西平联用时对儿童血药浓度的影响. 中国实用医药, 2013, 8(31): 176-177.
17. 王璐. 对影响拉莫三嗪稳态血药浓度的相关因素分析. 当代医药论丛, 2015, (4): 128-129.
18. 何艳玲, 和凡, 莫小兰, 等. 根据UGT1A4 142T>G基因多态性和丙戊酸血药浓度定量估算我国汉族癫痫儿童体内拉莫三嗪的血药浓度. 中国药房, 2017, 28(20): 2737-2742.
19. 和凡, 何艳玲, 祁俊华, 等. 合并抗癫痫药物对癫痫患儿拉莫三嗪血药浓度的影响. 儿科药学杂志, 2013, 19(9): 33-36.
20. 闫彩萍, 郝润喜. 癫痫儿童联用拉莫三嗪与丙戊酸时血药浓度观察. 山西医科大学学报, 2013, 44(12): 971-972.
21. 李丹, 黄绍平. 拉莫三嗪血药浓度与剂量合并用药和年龄关系研究. 中国实用儿科杂志, 2014, 29(10): 763-765.
22. 王威, 陈文伟, 褚燕琦, 等. 联用丙戊酸对儿童和成人癫痫患者拉莫三嗪血药浓度的影响. 临床药物治疗杂志, 2018, 16(11): 56-60.
23. 陈亚南, 徐善森, 邱枫, 等. 钠离子通道基因与转运体基因多态性对拉莫三嗪血药浓度的影响. 中国临床药理学杂志, 2016, 32(22): 2069-2072.
24. 贾莉, 周明明, 李红健, 等. 新疆地区维吾尔族, 汉族癫痫患儿拉莫三嗪血药浓度对比分析. 儿科药学杂志, 2015, 21(1): 34-36.
25. 包军, 何英, 苏渊, 等. 影响拉莫三嗪稳态血药浓度的相关因素研究. 中华儿科杂志, 2001, 39(8): 457-460.
26. 赵婷, 李红健, 王婷婷, 等. 新疆癫痫患儿拉莫三嗪稳态血药浓度影响因素的研究. 中国临床药理学杂志, 2021, 37(15): 1981-1984.
27. 楼江, 林能明, 陈玲, 等. 多个癫痫相关基因多态性与拉莫三嗪治疗儿童癫痫血药浓度的相关性. 中华全科医学, 2021, 19(1): 17-19,45.
28. Yasam VR, Jakki SL, Senthil V, et al. A pharmacological overview of lamotrigine for the treatment of epilepsy. Expert Rev Clin Pharmacol, 2016, 9(12): 1533-1546.
29. Weintraub D, Buchsbaum R, Resor SR, et al. Effect of antiepileptic drug comedication on lamotrigine clearance. Arch Neurol, 2005, 62(9): 1432-1436.
30. Miyagi SJ, Collier AC. Pediatric development of glucuronidation: the ontogeny of hepatic UGT1A4. Drug Metab Dispos, 2007, 35(9): 1587-1592.
31. 李臻, 王雁. UGT1A4142T>G基因多态性与中国癫痫患者拉莫三嗪血药浓度关系的荟萃分析. 中华医学杂志, 2018, 98(41): 3365-3370.

Chinese Journal of Evidence-Based Medicine

Influencing factors of plasma concentration of lamotrigine in the treatment of epilepsy in children: a systematic review

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