Objective  To analyze the influencing factors of individualized differences in plasma concentration of valproic acid, and to provide reference for clinical precision medication.

Methods  The clinical data of children with epilepsy treated with valproic acid from Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology were collected between January 2016 and August 2019. The CYP2C9 rs1057910 genotypes of the children were also detected. According to whether the concentration of valproic acid was more than 50 µg/mL, the children were divided into <50 µg/mL group and ≥50 µg/mL group, the differences in age, gender, concomitant medications, CYP2C9 genotype and the concentration of valproic acid were compared between the two groups. The effects of age, sex, CYP2C9 genotype, and concomitant medications on daily valproic acid dose, adjusted daily valproic acid dose, valproic acid concentration, and adjusted valproic acid concentration were further analyzed.

Results  A total of 179 children with epilepsy were enrolled, with 124 boys (69.3%) and 55 girls (30.7%), 112 cases in <50 µg/mL group and 67 cases in ≥50 µg/mL group. There were significant differences in daily valproic acid dose, adjusted daily valproic acid dose, adjusted concentration of valproic acid, vigabatranic acid, carbamazepine, and phenobarbital between two group. There were statistically significant differences in daily valproic acid dose, adjusted daily valproic acid dose, and adjusted concentration of valproic acid among different age groups, and there were statistically significant differences in daily valproic acid dose, adjusted daily valproic acid dose, and concentration of valproic acid between concomitant medication group and non-concomitant medication group. Multiple linear regression analysis showed that age and daily dose of valproic acid were independent risk factors for the plasma concentration of valproic acid.

Conclusion  Age and daily dose of valproic acid are the main factors affecting the plasma concentration of valproic acid. The dosage adjustment of valproic acid should be based on the comprehensive consideration of CYP2C9 genotype and age.

1.丁晶, 汪昕. 癫痫诊疗指南解读[J]. 临床内科杂志, 2016, 33(2): 142-144. [Ding J, Wang X. Interpretation of epilepsy diagnosis and treatment guidelines[J]. Journal of Clinical Internal Medicine, 2016, 33(2): 142-144.] DOI: 10.3969/j.issn.1001-9057.2016.02.025.

2.儿童癫痫持续状态诊断治疗的中国专家共识(2022)[J]. 癫痫杂志, 2022, 8(5): 383-389. [Chinese expert consensus on diagnosis and treatment of status epilepticus in children (2022)[J]. Journal of Epilepsy, 2022, 8(5): 383-389] DOI: 10.7507/2096-0247.202207002.

3.Gonzalez-Viana E, Sen A, Bonnon A, et al. Epilepsies in children, young people, and adults: summary of updated NICE guidance[J]. BMJ, 2022, 378: o1446. DOI: 10.1136/bmj.o1446.

4.罗琼, 那尔布力·巴合提别克, 茹凉, 等. 丙戊酸钠不同血药浓度对癫痫病患儿中毒反应发生率的影响[J]. 西部医学, 2018, 30(9): 1348-1352. [Luo Q, Naerbulio Bahetibieke, Ru L, et al. Effect of different concentrations of sodium valproate on the incidence of toxic reaction in children with epilepsy[J]. Medical Journal of West China, 2018, 30(9): 1348-1352.] DOI: 10.3969/j.issn.1672-3511.2018.09.021.

5.果伟, 张玲, 王刚. 中国精神科治疗药物监测临床应用专家共识（2022年版）[J]. 神经疾病与精神卫生, 2022, 22(8): 601-608. [Guo W, Zhang L, Wang G. Expert consensus on clinical application of psychiatric therapeutic drug monitoring in China (2022 edition)[J]. Journal of Neuroscience and Mental Health, 2022, 22(8): 601-608.] DOI: 10.3969/j.issn.1009-6574. 2022.08.013.

6.Silva MF, Aires CC, Luis PB, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review[J]. J Inherit Metab Dis, 2008, 31(2): 205-216. DOI: 10.1007/s10545-008-0841-x.

7.Monostory K, Nagy A, Tóth K, et al. Relevance of CYP2C9 function in valproate therapy[J]. Curr Neuropharmacol, 2018, 17(1): 99-106. DOI: 10.2174/1570159x15666171109143654.

8.Strassburg CP. Developmental aspects of human hepatic drug glucuronidation in young children and adults[J]. Gut, 2002, 50(2): 259-265. DOI: 10.1136/gut.50.2.259.

9.Fang H, Wang X, Hou K, et al. The association of adjusted plasma valproic acid concentration with CYP2C9 gene polymorphism in patients with epilepsy: a systematic review and meta-analysis[J]. Ann Transl Med, 2021, 9(10): 846. DOI: 10.21037/atm-21-1459.

10.Ho PC, Abbott FS, Zanger UM, et al. Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes[J]. Pharmacogenomics J, 2003, 3(6): 335-342. DOI: 10.1038/sj.tpj.6500210.

11.Wang C, Wang P, Yang LP, et al. Association of CYP2C9, CYP2A6, ACSM2A, and CPT1A gene polymorphisms with adverse effects of valproic acid in Chinese patients with epilepsy[J]. Epilepsy Res, 2017, 132: 64-69. DOI: 10.1016/j.eplepsyres.2017.02.015.

12.王俊, 李思婵, 高柳柳, 等. 丙戊酸对拉莫三嗪在癫痫患儿体内药动学及给药剂量的影响[J].中国新药与临床杂志, 2022, 41(10): 605-611. [Wang J, Li SC, Gao LL, et al. Effects of valproic acid on pharmacokinetics and dosage of lamotrigine in children with epilepsy[J]. Chinese Journal of New Drugs and Clinical Remedies, 2022, 41(10): 605-611.] DOI: 10.14109/j.cnki.xyylc.2022.10.06.

13.Li RT, Chen ZY, Tang SY, et al. Association of Valproic acid and its main metabolites' plasma concentrations with clinical outcomes among epilepsy patients: a 10-year retrospective study based on therapeutic drug monitoring[J]. Drug Metab Dispos, 2024, 52(3): 210-217. DOI: 10.1124/dmd.123.001539.

14.常钊, 李依琪, 张胜男, 等. 癫痫患儿丙戊酸钠血药浓度特点及复发风险因素分析[J]. 中国药师, 2022, 25(4): 640-644. [Chang  Z, Li YQ, Zhang SN, et al. Serum concentration characteristics of valproate and recurrent risk factors in children with epilepsy[J]. China Pharmacist, 2022, 25(4): 640-644.] DOI: 10.19962/j.cnki.issn1008-049X.2022.04.014.

15.陈宏镇, 谢焕山, 陈超端, 等. 基于治疗药物监测的丙戊酸钠缓释片血药浓度影响因素分析[J]. 中国临床药理学杂志, 2020, 36(10): 1216-1219. [Zhen HZ, Shan HS, Chen  CD, et al. Influential factors of serum concentration for sodium valproate sustained release tablets: evidence from a routine therapeutic drug monitoring service[J]. The Chinese Journal of Clinical Pharmacology, 2020, 36(10): 1216-1219.] DOI: 10.13699/j.cnki.1001-6821.2020.10.013.

16.丁靖, 蒙卓成, 张燕, 等. 2019—2021年2992例次丙戊酸治疗药物监测结果的回顾性分析[J]. 中国全科医学, 2023, 26(23): 2923-2929. [Ding J, Meng ZC, Zhang Y, et al. Retrospective analysis of 2992 times of therapeutic drug monitoring of valproic acid from 2019 to 2021[J]. Chinese General Practice, 2023, 26(23): 2923-2929.] DOI: 10.12114/j.issn.1007-9572.2023.0016.

17.Ghodke-Puranik Y, Thorn CF, Lamba JK, et al. Valproic acid pathway[J]. Pharmacogenet Genomics, 2013, 23(4): 236-241. DOI: 10.1097/FPC.0b013e32835ea0b2.

18.Methaneethorn J. A systematic review of population pharmacokinetics of valproic acid[J]. Br J Clin Pharmacol, 2018, 84(5): 816-834. DOI: 10.1111/bcp.13510.

19.李乾琛. 卡马西平, 拉莫三嗪和司替戊醇对丙戊酸及其代谢物药动学的影响[D]. 2021. DOI: 10.27111/d.cnki.ghyku.2021. 000139.

20.Lan X, Mo K, Nong L, et al. Factors influencing sodium valproate serum concentrations in patients with epilepsy based on logistic regression analysis[J]. Med Sci Monit, 2021, 27: e934275. DOI: 10.12659/MSM.934275.

21.Iapadre G, Balagura G, Zagaroli L, et al. Pharmacokinetics and drug interaction of antiepileptic drugs in children and adolescents[J]. Pediatric Drugs, 2018, 20(5): 429-453. DOI: 10.1007/s40272-018-0302-4.

22.Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients[J]. Clin Pharmacokinetics, 1995, 29(4): 257-286. DOI: 10.2165/00003088-199529040-00005.

23.Maglalang PD, Wen J, Hornik CP, et al. Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population[J]. Clin Transl Sci, 2024, 17(4): e13793. DOI: 10.1111/cts.13793.

24.Cloyd JC, Fischer JH, Kriel RL, et al. Valproic acid pharmacokinetics in children. IV. effects of age and antiepileptic drugs on protein binding and intrinsic clearance[J]. Clin Pharmacol Ther, 1993, 53(1): 22-29. DOI: 10.1038/clpt.1993.5.

25.Sánchez-Alcaraz A, Quintana MB, López E, et al. Valproic acid clearance in children with epilepsy[J]. J Clin Pharm Ther, 1998, 23(1): 31-34. https://pubmed.ncbi.nlm.nih.gov/9756109/.

26.van Dijkman SC, de Jager NCB, Rauwé WM, et al. Effect of age-related factors on the pharmacokinetics of lamotrigine and potential implications for maintenance dose optimisation in future clinical trials[J]. Clin Pharmacokinet, 2018, 57(8): 1039-1053. DOI: 10.1007/s40262-017-0614-5.

27.Tóth K, Bűdi T, Kiss Á, et al. Phenoconversion of CYP2C9 in epilepsy limits the predictive value of CYP2C9 genotype in optimizing valproate therapy[J]. Personalized Med, 2015, 12(3): 199-207. DOI: 10.2217/pme.14.82.

28.Bűdi T, Tóth K, Nagy A, et al. Clinical significance of CYP2C9-status guided valproic acid therapy in children[J]. Epilepsia, 2015, 56(6): 849-855. DOI: 10.1111/epi.13011.