{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T17:11:55Z","timestamp":1777050715051,"version":"3.51.4"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold> The aim of this study was to establish a population pharmacokinetic (PPK) model of valproic acid (VPA) in pediatric patients with epilepsy in southern China, and provide guidance for individualized medication of VPA therapy.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A total of 376 VPA steady-state trough concentrations were collected from 103 epileptic pediatric patients. The PPK parameter values for VPA were calculated by using the nonlinear mixed-effects modeling (NONMEM) method, and a one-compartment model with first-order absorption and elimination processes was applied. Covariates included demographic information, concomitant medications and selected gene polymorphisms. Goodness-of-fit (GOF), bootstrap analysis, and visual predictive check (VPC) were used for model evaluation. In addition, we used Monte Carlo simulations to propose dose recommendations for different subgroup patients.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A significant effect of the patient age and <jats:italic>ABCB1<\/jats:italic> genotypes was observed on the VPA oral clearance (CL\/F) in the final PPK model. Compared with patients with the <jats:italic>ABCB1<\/jats:italic> rs3789243 AA genotype, CL\/F in patients with GG and AG genotypes was increased by 8% and reduced by 4.7%, respectively. The GOF plots indicated the satisfactory predictive performance of the final model, and the evaluation by bootstrap and VPC showed that a stable model had been developed. A table of individualized dosing regimens involving age and <jats:italic>ABCB1<\/jats:italic> genotype was constructed based on the final PPK model.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> This study quantitatively investigated the effects of patient age and <jats:italic>ABCB1<\/jats:italic> rs3789243 variants on the pharmacokinetic variability of VPA. The PPK models could be beneficial to individual dose optimization in epileptic children on VPA therapy.<\/jats:p>","DOI":"10.3389\/fphar.2022.1037239","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T06:36:30Z","timestamp":1669358190000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism"],"prefix":"10.3389","volume":"13","author":[{"given":"Xianhuan","family":"Shen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieluan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhou","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaodong","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijuan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenshu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomei","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1007\/s10928-005-0083-6","article-title":"Inherent correlation between dose and clearance in therapeutic drug monitoring settings: Possible misinterpretation in population pharmacokinetic analyses","volume":"32","author":"Ahn","year":"2005","journal-title":"J. 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