基于代谢酶、转运体和受体基因多态性的拉莫三嗪治疗癫痫PKPD研究

Lamotrigine is the first-line drug for primary treatment of epilepsy. Large inter-individual variability of serum concentration and drug effect is observed in clinical practice. However, the dominant causes of the variability have not been clarified. In the current study, we speculate that the SNP polymorphism of the metabolic enzyme UGT1A, transporter MDR1 and receptor SCN1A may be the main causes of the variability. We plan to explain and quantify the variability of lamotrigine from the genetic polymorphism point of view using a combined method of pharmacogenomics and PKPD modeling. Based on this, the rational dose for the patients with different gene mutations will be provided. Firstly, we established the PKPD model with the serum concentration and counts of seizures based on the Poisson's distribution; secondly, by comparing the ratio of concentration in cerebrospinal fluid and serum between the responsers and non-responsers, the low pemeabality of lamotrigine through blood brain barrier derived from the mutation of the transportor MDR1 locus may be confirmed; finally, modeling and simulation based on the final PKPD model would predict the effective therapeutic range to guide rational application of lamotrigine. The results of this study could predict the drug effect on different regimens to determine the rational dose, which would provide a theoretical basis for the personalized therapy and clinical application of lamotrigine.

拉莫三嗪是一线的广谱抗癫痫药物，临床发现患者间血药浓度与临床疗效差异较大，导致临床疗效差异的主要因素目前尚不明确。我们推测与拉莫三嗪药动学药效学相关的主要代谢酶UGT1A、转运体MDR1和作用受体SCN1A的关键SNP位点是导致其个体差异的主要原因。本研究拟将药物基因组学与PKPD模型方法相结合，从基因多态性层面解释并量化拉莫三嗪疗效的个体差异，确定不同基因突变所需的治疗剂量。首先应用泊松分布理论建立癫痫患者拉莫三嗪血药浓度与癫痫发作次数的PKPD模型，量化SNP位点突变对药物浓度以及抗癫痫疗效的影响；其次考察有效组和无效组拉莫三嗪脑脊液/血清浓度比值，明确减低药物透过血脑屏障造成药物疗效不佳的转运体MDR1位点；最后通过模型仿真预测不同基因型患者的治疗浓度范围来指导合理用药。该研究结果能预测不同给药方案产生的药物疗效，迅速确定药物合理剂量，对癫痫患者的个体化治疗具有理论意义和临床应用价值

拉莫三嗪是一线的广谱抗癫痫药物，临床应用发现患者服用拉莫三嗪后个体间血药浓度与临床疗效差异较大，并且较高的拉莫三嗪血药浓度容易导致皮肤不良反应，部分可转为严重威胁生命的皮肤反应，其中合并使用丙戊酸、剂量递增过快是引起皮肤不良反应的重要因素，如何合理使用拉莫三嗪是本研究主要研究内容。鉴于临床血药浓度数据均为稀疏型数据，同时患者服药和采血时间无法严格控制，故本研究采用群体药代动力学方法构建符合中国人群药代动力学特征的拉莫三嗪群体药代动力学模型，同时量化各个关键影响因素对拉莫三嗪药代动力学影响。结果显示拉莫三嗪在体内的分布符合一室开放模型，合并用药和基因多态性是影响拉莫三嗪药动学药效学最主要因素，其中合用丙戊酸可降低拉莫三嗪清除率38.5%，合用利福平可增加拉莫三嗪清除率64.7%，携带SLC22A1（rs628031）AA基因型患者拉莫三嗪体内清除率可降低52.5%，携带ABCG2-34G>A（rs2231137）AA基因型患者拉莫三嗪体内表观分布容积减低 42.0%，携带MDR1-2677G（rs2032582）TT基因型和 -C3435T（rsrs1045642）TT基因型患者拉莫三嗪体内分布容积增大136.0%。通过模型仿真预测不同基因型和合并用药的患者在不同给药方案达到拉莫三嗪血药浓度治疗窗（3-8mg/L）所需要的药物剂量。根据仿真结果，常规患者服用200 mg/d即能达治疗窗，而合并丙戊酸后需减量至100 mg/d；若合并利福平则应将剂量增加至450 mg/d；若是MDR1-2677G（rs2032582）TT基因型和 -C3435T（rsrs1045642）TT基因型患者则需调整至150 mg/d；SLC22A1（rs628031）AA基因型患者需服用75 mg/d；ABCG2-34G>A（rs2231137）AA基因型患者需服用300 mg/d。结合治疗药物监测及模型仿真技术可以估算患者的合理用药剂量，为拉莫三嗪的个体化治疗提供服务。