抽动障碍儿童的阿立哌唑代谢比与CYP2D6基因多态性的关系及对剂量-暴露的影响  

The relationship between Aripiprazole metabolic ratio and CYP2D6 gene polymorphism in children with tic disorders and its influence on dose-exposure

作　　者：陈惠敏 汪洋[2] 高柳柳 刘智胜[1] Chen Huimin;Wang Yang;Gao Liuliu;Liu Zhisheng(Department of Neurology,Wuhan Children's Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430016,China;Department of Pharmacy,Wuhan Children's Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430016,China)

机构地区：[1]华中科技大学同济医学院附属武汉儿童医院神经内科,武汉430016 [2]华中科技大学同济医学院附属武汉儿童医院药学部,武汉430016

出　　处：《中华实用儿科临床杂志》2024年第11期842-847,共6页Chinese Journal of Applied Clinical Pediatrics

基　　金：国家重点研发计划(2016YFC1306202);湖北省科技计划立项项目-儿童神经发育障碍临床医学研究中心(2022DCC020)。

摘　　要：目的探讨抽动障碍(TD)儿童阿立哌唑(ARI)体内代谢比与CYP2D6基因多态性的关系及对剂量-暴露(DE)的影响,促进精准用药。方法本研究采用真实世界观察性研究设计,研究对象为2021年1月至2024年1月武汉儿童医院神经内科就诊的81例TD患儿,收集患儿口服ARI后的原形药物及主要代谢产物脱氢阿立哌唑(DARI)水平、CYP2D6单核苷酸基因多态性(SNP)检测数据和临床资料,采用受试者工作特征(ROC)曲线分析DARI/ARI代谢比值(MR)与CYP2D6代谢型的关系。采用群体建模方法建立ARI给药剂量与稳态谷浓度之间的DE模型,分别引入分析CYP2D6代谢型、MR及体重对DE关系的影响。采用拟合优度图(GOF)、直观预测检验(VPC)和预测误差分析验证DE模型的预测性能。结果ROC曲线分析显示,MR与CYP2D6代谢型存在相关性,CYP2D6超快代谢型(UM)患儿MR敏感界值切点(Cut-point)为0.399,中间代谢型(IM)患儿MR的Cut-point为0.252,基于此将患儿分为3类,MR TYPEⅠ:MR≥0.399、MR TYPEⅡ:0.252<MR<0.399、MR TYPEⅢ:MR≤0.252。本研究共建立3种线性DE模型,除体重外,3种模型还分别引入CYP2D6代谢型、MR分类、MR连续变量对DE线性关系斜率产生影响。GOF、VPC和预测误差统计显示3种模型的预测准确度较好,经贝叶斯校正的浓度预测准确度优于群体预测浓度。结论MR与CYP2D6代谢型密切相关,MR可间接反映ARI的体内代谢速率从而影响DE关系,临床可监测并根据MR值调整用药方案。ObjectiveTo investigate the relationship between the in vivo metabolic ratio(MR)of Aripiprazole(ARI)and CYP2D6 gene polymorphism in children with tic disorders(TD)and its effect on dose-exposure(DE),so as to promote precision drug use.MethodsIn this study,a real-world observational study design was used to collect 81 children with TD who visited the Department of Neurology of Wuhan Children′s Hospital from January 2021 to January 2024,the concentration of the prototype drug and the main metabolite Dehydroaripiprazole(DARI),the detection data of CYP2D6 single nucleotide gene polymorphism(SNP)and clinical data were collected,and the relationship between the DARI/ARI metabolic ratio(MR)and CYP2D6 metabolic type was analyzed by the receiver operating characteristic(ROC)curve.A DE model between ARI dose and steady-state trough concentration was established by population modeling,and the effects of CYP2D6 metabolic type,MR and body weight on DE were analyzed.Goodness-of-fit diagram(GOF),visual predictive check(VPC)and prediction error analysis were used to verify the prediction performance of the DE model.ResultsROC analysis showed that there was a correlation between MR and CYP2D6 metabolic type,the MR sensitivity cut-point of CYP2D6 ultrafast metabolic(UM)patients was 0.399,and the cut-point of MR in intermediate metabolic(IM)patients was 0.252.Based on this,the patients were divided into three categories:MR TYPEⅠ:MR≥0.399,MR TYPEⅡ:0.252<MR<0.399,and MR TYPEⅢ:MR≤0.252.In this study,three linear DE models were established,and in addition to body weight,the three models also introduced CYP2D6 metabolic type,MR classification,and MR continuous variables to affect the slope of DE linear relationship.The GOF,VPC and prediction error statistics showed that the prediction accuracy of the three models was better,and the accuracy of Bayesian-corrected concentration prediction was better than that of the population prediction.ConclusionsMR is closely related to CYP2D6 metabolic type.MR can indirectly reflect the in

关 键 词：儿童 抽动障碍 阿立哌唑 脱氢阿立哌唑 代谢比 CYP2D6 

分 类 号：R749.94[医药卫生—神经病学与精神病学]