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.	中華醫學會兒科學分會神經學組. 兒童癲癇長程管理專家共識. 中華兒科雜志, 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.	聯合國兒童基金會. 兒童權利公約, 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.	王秋寧. 代謝酶和轉運體基因多態性對拉莫三嗪代謝及藥物相互作用的影響. 沈陽: 中國醫科大學, 2015.
16.	閆彩萍, 郝潤喜. 拉莫三嗪和卡馬西平聯用時對兒童血藥濃度的影響. 中國實用醫藥, 2013, 8(31): 176-177.
17.	王璐. 對影響拉莫三嗪穩態血藥濃度的相關因素分析. 當代醫藥論叢, 2015, (4): 128-129.
18.	何艷玲, 和凡, 莫小蘭, 等. 根據UGT1A4 142T>G基因多態性和丙戊酸血藥濃度定量估算我國漢族癲癇兒童體內拉莫三嗪的血藥濃度. 中國藥房, 2017, 28(20): 2737-2742.
19.	和凡, 何艷玲, 祁俊華, 等. 合并抗癲癇藥物對癲癇患兒拉莫三嗪血藥濃度的影響. 兒科藥學雜志, 2013, 19(9): 33-36.
20.	閆彩萍, 郝潤喜. 癲癇兒童聯用拉莫三嗪與丙戊酸時血藥濃度觀察. 山西醫科大學學報, 2013, 44(12): 971-972.
21.	李丹, 黃紹平. 拉莫三嗪血藥濃度與劑量合并用藥和年齡關系研究. 中國實用兒科雜志, 2014, 29(10): 763-765.
22.	王威, 陳文偉, 褚燕琦, 等. 聯用丙戊酸對兒童和成人癲癇患者拉莫三嗪血藥濃度的影響. 臨床藥物治療雜志, 2018, 16(11): 56-60.
23.	陳亞南, 徐善森, 邱楓, 等. 鈉離子通道基因與轉運體基因多態性對拉莫三嗪血藥濃度的影響. 中國臨床藥理學雜志, 2016, 32(22): 2069-2072.
24.	賈莉, 周明明, 李紅健, 等. 新疆地區維吾爾族, 漢族癲癇患兒拉莫三嗪血藥濃度對比分析. 兒科藥學雜志, 2015, 21(1): 34-36.
25.	包軍, 何英, 蘇淵, 等. 影響拉莫三嗪穩態血藥濃度的相關因素研究. 中華兒科雜志, 2001, 39(8): 457-460.
26.	趙婷, 李紅健, 王婷婷, 等. 新疆癲癇患兒拉莫三嗪穩態血藥濃度影響因素的研究. 中國臨床藥理學雜志, 2021, 37(15): 1981-1984.
27.	樓江, 林能明, 陳玲, 等. 多個癲癇相關基因多態性與拉莫三嗪治療兒童癲癇血藥濃度的相關性. 中華全科醫學, 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基因多態性與中國癲癇患者拉莫三嗪血藥濃度關系的薈萃分析. 中華醫學雜志, 2018, 98(41): 3365-3370.

1. 中華醫學會兒科學分會神經學組. 兒童癲癇長程管理專家共識. 中華兒科雜志, 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. 聯合國兒童基金會. 兒童權利公約, 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. 王秋寧. 代謝酶和轉運體基因多態性對拉莫三嗪代謝及藥物相互作用的影響. 沈陽: 中國醫科大學, 2015.
16. 閆彩萍, 郝潤喜. 拉莫三嗪和卡馬西平聯用時對兒童血藥濃度的影響. 中國實用醫藥, 2013, 8(31): 176-177.
17. 王璐. 對影響拉莫三嗪穩態血藥濃度的相關因素分析. 當代醫藥論叢, 2015, (4): 128-129.
18. 何艷玲, 和凡, 莫小蘭, 等. 根據UGT1A4 142T>G基因多態性和丙戊酸血藥濃度定量估算我國漢族癲癇兒童體內拉莫三嗪的血藥濃度. 中國藥房, 2017, 28(20): 2737-2742.
19. 和凡, 何艷玲, 祁俊華, 等. 合并抗癲癇藥物對癲癇患兒拉莫三嗪血藥濃度的影響. 兒科藥學雜志, 2013, 19(9): 33-36.
20. 閆彩萍, 郝潤喜. 癲癇兒童聯用拉莫三嗪與丙戊酸時血藥濃度觀察. 山西醫科大學學報, 2013, 44(12): 971-972.
21. 李丹, 黃紹平. 拉莫三嗪血藥濃度與劑量合并用藥和年齡關系研究. 中國實用兒科雜志, 2014, 29(10): 763-765.
22. 王威, 陳文偉, 褚燕琦, 等. 聯用丙戊酸對兒童和成人癲癇患者拉莫三嗪血藥濃度的影響. 臨床藥物治療雜志, 2018, 16(11): 56-60.
23. 陳亞南, 徐善森, 邱楓, 等. 鈉離子通道基因與轉運體基因多態性對拉莫三嗪血藥濃度的影響. 中國臨床藥理學雜志, 2016, 32(22): 2069-2072.
24. 賈莉, 周明明, 李紅健, 等. 新疆地區維吾爾族, 漢族癲癇患兒拉莫三嗪血藥濃度對比分析. 兒科藥學雜志, 2015, 21(1): 34-36.
25. 包軍, 何英, 蘇淵, 等. 影響拉莫三嗪穩態血藥濃度的相關因素研究. 中華兒科雜志, 2001, 39(8): 457-460.
26. 趙婷, 李紅健, 王婷婷, 等. 新疆癲癇患兒拉莫三嗪穩態血藥濃度影響因素的研究. 中國臨床藥理學雜志, 2021, 37(15): 1981-1984.
27. 樓江, 林能明, 陳玲, 等. 多個癲癇相關基因多態性與拉莫三嗪治療兒童癲癇血藥濃度的相關性. 中華全科醫學, 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基因多態性與中國癲癇患者拉莫三嗪血藥濃度關系的薈萃分析. 中華醫學雜志, 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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