癫痫患者丙戊酸钠代谢基因多态性影响个体化治疗的群体PK-PD研究

Sodium valproate (Valproate, VPA) is the preferred drug of various epileptic seizures in clinical medicine, but drug dose has a significant impact on plasma concentration, also with considerable individual differences and difficult to master the drug dose. So, in the treatment of epilepsy, it has significant meaning to advance blood concentration monitoring of the patients treated with evaporate. It has become a more deep-seated problem of clinical individualized treatment and rational administration about how to establish a quantitative relationship between blood drug level and efficacy. The CYP450 gene polymorphism is the main genetic factors to affect antiepileptic drug metabolism. Furthermore it is an important cause of the individual differences. Bring CYP450 gene polymorphism factors in population pharmacokinetics model to quantify the effects of the antiepileptic drug metabolism, and according to the different genotypes to select the initial dose, to promote individualized treatment. The entry point for the topics is valproate, carry out VPA clinical trials of valproate through multidisciplinary partnerships, to detect patient plasma concentration, to study metabolic gene polymorphism and drug effect of patients ,to establish a population PK-PD mathematical model ,bring a comprehensive contact of genetic factors - non-genetic factors - pharmacokinetics - pharmacodynamic, design a optimization program about individualized dose, provide a new quantitative research thinking about clinical pharmacology of personalized medicine, also provide a favorable evidence for VPA clinical rational use of valproate. Achieve a real sense of individualized medication.

丙戊酸钠（VPA）是多种癫痫发作类型的首选药物，但其血药浓度与剂量关系复杂，个体差异大，临床剂量难以把握，必须进行血药浓度监测。如何建立血药浓度和疗效的定量关系，成为临床个体化治疗与合理用药的更深层次的问题。CYP450基因多态性是影响抗癫痫药物代谢的主要遗传因素，是个体差异的重要原因，将CYP450基因多态性的因素引入群体药代动力学的模型，对抗癫痫药物代谢的影响进行量化，根据不同基因型选择不同的初始剂量，促进个体化治疗。本课题以VPA为切入口，采用多学科交叉的方法，实施VPA临床试验，检测病人血药浓度、研究代谢基因多态性及药物效应等指标，建立群体PK-PD数学模型，将"遗传因素－非遗传因素－药动学－药效学"综合联系起来，分析个体化剂量与基因多态性关系，设计个体化剂量优化方案，为临床药理学的个体化治疗提供新的定量研究思路，并为VPA临床合理用药提供有利证据，实现真正意义的个体化治疗。

本课题以丙戊酸钠为切入口，用LC-MS/MS法检测癫痫患者VPA及其代谢产物血药浓度，与临床使用的金标准----酶联免疫分析法（CMIA）相比，VPA血药浓度一致性良好，相关系数为0.9700，证明本法可以取代CMIA法。建立群体PK-PD数学模型，通过模型的优化确定最终模型为CL=TvCL*exp(ηCL)，应用自举法验证该模型，发现该模型稳定性良好。同时将代谢基因多态性及药物效应等指标纳入考察，研究发现CYP2C19*2基因正常组与突变组对癫痫患者的VPA的代谢产物血药浓度差异有统计学意义（P<0.05），该差异是造成VPA代谢产物浓度个体差异的可能因素，因此推荐该基因成为临床检测项目。本课题将“遗传因素－非遗传因素－药动学－药效学”综合联系起来，分析个体化剂量与基因多态性及其他影响因素精密的定量关系，设计个体化剂量优化方案及临床应用简表，为丙戊酸钠临床合理用药提供有利证据，实现真正意义“量体裁衣”式的精准化药物治疗。. 综上所述，本课题通过研究，完成预期目标，明确LC-MS/MS法监测VPA及代谢产物浓度，推荐CYP2C19*2成为临床检测项目。本研究结果对临床癫痫病人个体化给药具有重要的指导意义。项目实施期间共发表标注资助的论文7篇，其中SCI论文4篇，中文核心期刊2篇，硕士研究生论文1篇，培养硕士研究生2名。