个体化医学在肿瘤治疗领域的应用(安徽)剖析.ppt

五、FDA批准有药物基因组学内容的抗肿瘤药物 Irinotecan Pathway Enteric bacterial –glucuronidase regenerates gut local tissue damage and diarrhea SN-38 : 7-ethyl-10-hydroxycamptothecin bile SN-38 FDA advisory committee: a reduction in the starting dose by at least one level [15–25%] should be considered for patients known to be homozygous for the UGT1A1*28 allele.” /bbs/topics/NEWS/2005/NEW01220.html UGT1A1 gained recognition as the first pharmacogenetic test to achieve FDA approval for use in conjunction with a specific drug (irinotecan) ? Biomarker Representative Label Drug CYP2C9 Variants CYP2C9 Variants PM and EM genotypes and drug exposure; “已知或怀疑是P450 2C9弱代谢型的患者，使用塞来昔布要谨慎，因为血药浓度会异常升高” Celecoxib 塞来昔布（西乐葆） ? Biomarker Representative Label? Drug CYP2D6 Variants CYP2D6 Variants CYP2D6活性低者，其治疗效果可能较差 Tamoxifen; 他莫昔芬 ? Biomarker Representative Label? Drug DPD Deficiency Deficiency of Dihydropyrimidine Dehydrogenase: 1、“与5FU有关的罕见、意外和严重的毒性（如口腔炎、腹泻、中性粒细胞减少和神经毒性），与DPD活性缺失有关。不能排除DPD活性降低与5FU潜在致命毒性作用增加的关联。” 禁用：DPD缺失者 2、（1）同1。 （2）若DPD活性持续降低，终止5FU治疗 1、Capecitabine 卡培他滨 2、Fluorouracil 氟尿嘧啶 乳腺癌 ? Biomarker Representative Label? Drug Her2/neu Over-expression Overexpresion of Her2/neu necessary for selection of patients appropriate for drug therapy 1、“检测HER2蛋白表达，是选择赫赛汀治疗的必要条件。” 2、拉帕替尼用于HER2蛋白表达阳性患者 1、Trastuzumab 曲妥珠单抗 2、Lapatinib 拉帕替尼 乳腺癌 白血病 ? Biomarker Representative Label? Drug Philadelphia Chromosome-positive responders Philadelphia (Ph1) chromosome presence (effective) – 1、“白消安对缺乏费城（Ph1）染色体的慢粒患者效果较小。此药对慢粒进入急性期的患者无益处” 2、“达沙替尼用于对其他治疗有抗性或不耐受的费城染色体阳性成人急性淋巴细胞白血病 (Ph+ ALL)” 3、“尼罗替尼用于对其他治疗有抗性或不耐受的费城染色体阳性成人慢性髓性白血病（Ph+ CML）” 1、Busulfan 白消安 2、Dasatinib 达沙替尼 3、Nilotinib 尼罗替尼 UGT1A1 variants with alternate context Pharmacogenomics (safety)“尼罗替尼可增加胆红素水平。在UGT1A1 (TA)7/(TA)7 基因型 (UGT1A1*28) 的患者，出现最严重的高胆红素血症[See Warnings and Precautions].” Nilotinib 尼罗替尼 白血病 ? Biomarker Representative Label? Drug PML/RAR alpha gene expression (Retinoic acid recepto