苯妥英钠预防颅脑术后早期癫的群体药动学及个体化给药方案设计  

Population pharmacokinetics and individualized medication of phenytoin for the prophylaxis of early epilepsy after craniocerebral operation

作　　者：王川[1] 刘萌[2] 雷兆锦[3] 万经海[4] 黄永安[5] 李忠东[1] 

机构地区：[1]空军总医院药学部,北京100142 [2]安徽省六安市中医院药剂科,安徽六安237006 [3]解放军第四一一医院特诊科,上海200081 [4]中国医学科学院肿瘤医院神经外科,北京100021 [5]空军总医院神经外科,北京100142

出　　处：《药学服务与研究》2016年第6期418-423,共6页Pharmaceutical Care and Research

基　　金：首都医学发展基金重点项目(2009-2055)

摘　　要：目的:建立苯妥英钠预防颅脑术后早期癫的群体药动学(population pharmacokinetics,PPK)模型,为精准设计个体化给药方案提供参考依据。方法:按入选标准收集颅内恶性肿瘤且需要手术的病人112例,术前以PCR扩增的方法检测CYP2C9和CYP2C19基因型。术后第1天(d 1)开始口服苯妥英钠,以荧光偏振免疫法测定苯妥英钠的血药浓度。用非线性混合效应模型(non-linear mixed effects model,NONMEM)建立最终PPK模型,采用Bootstraps法进行内部验证。以最终PPK模型设计50例病人的苯妥英钠个体化给药方案并应用于临床。结果:112例病人中,强代谢型、中代谢型和弱代谢型组病人所需苯妥英钠的剂量分别为8.51、8.01和6.91mg·kg^(-1)·d^(-1),拟合的Vm参数值分别为27.608、20.807和18.945mg/h,Km参数值分别为4.27、3.85和1.70mg/L。内部验证显示模型稳定、可靠。以该模型设计的个体化给药方案,病人术后d 4和d 7谷浓度达到有效治疗范围的比例分别为78.72%(37/47)和80.00%(36/45),比112例病人d 4达到有效治疗范围的比例18.27%(17/93)和d 7的41.96%(47/112)显著提高(P<0.000 1)。结论:本研究建立的最终PPK模型,可为设计苯妥英钠预防颅脑术后早期癫的个体化给药方案提供参考。Objective： To establish population pharmacokinetics（PPK） model of phenytoin for the prophylaxis of early seizure after craniocerebral operation,in order to provide reference for designing individual administration regimen of phenytoin. Methods： Totally, 112 patients with intracranial malignant tumor, who required surgery, were enrolled according to the inclusion criteria. Genotypes of CYP2C9 and CYP2C19 were detected by polymerase chain reaction（PCR） before operation. Phenytoin was orally administered to the patients on the first day （d 1）after operation. Serum concentrations of phenytoin were determined by fluorescence polarization immunoassay （FPIA）. The final PPK model was established by non-linear mixed effects model （NONMEM） and internal validation was performed by Bootstraps. Individual dosage regimens of phenytoin for the 50 patients were designed according to the final PPK model. Results： The recommended doses of extensive metabolizers, intermediate metabolizers and poor metaholizers in the 112 patients were 8.51, 8.01 and 6.91 mg · kg-1 · d-1 , respectively. The estimated values of Vm were 27. 608,20. 807 and 18. 945 mg/h and the values of Km were 4.27, 3.85 and 1.70 mg/L,respectively. Results of the internal validation by Bootstraps showed that the final model was stable and reliable. Individualized dosage regimens for the 50 patients were designed by the final model. The percentages of effective trough concentrations were 78. 72 （37/47,4 days after operation） and 80.00 %（36/45,7 days after operation）, respectively, which were significantly higher than 18.27% （17/93） and 41.96%（47/112） in the model group of 112 patients （P〈0. 000 1）. Conclusion.. The final PPK model of phenytoin established in this study may provide reference for the design of individualized regimen of phenytoin that might prevent early seizure after craniocerebral operation.

关 键 词：苯妥英钠 群体药代动力学 个体化给药 癫痢 非线性混合效应模型 基因型 

分 类 号：R969.1[医药卫生—药理学] R971.6[医药卫生—药学]