临床药理学总论资料文档.pptVIP

Genetic determined drug metabolism 与药物作用相关蛋白的基因多态性多有基因剂量效应 巯嘌呤(6-MP)/咪唑嘌呤: TPMT (硫嘌呤甲基转移酶) 巯嘌呤 (6-MP) 代谢 根据病人TPMT基因型选择剂量减少毒性 Potential of UGT Testing to Inform Dosing UGT1A1*28 alters irinotecan neutropenic/activity 35.7 16.3 8.6 0 5 10 15 20 25 30 35 40 45 50 6/6 6/7 7/7 P=0.007 UGT1A1 genotype % grade 4/5 neutropenia n=524 41.9 33.8 14.3 5 10 20 6/6 6/7 7/7 UGT1A1 genotype 0 15 25 30 35 40 45 Objective response (%) P=0.045 McLeod H. et al, 2003. n=524 突变纯合子和杂合子的个体发生严重不良反应的风险增加7倍 4级粒细胞减少症发生率(%) 6/6 6/7 7/7 50% 12.5% 0% 100 50 0 10% ALL 基因型频率： 10% 40% 50% 伊立替康ADRs发生率与UGT1A1*28频率相关 All Patients with Same Diagnosis (10% risk) PGx profile (7/7) for high risk (50%): treat with alternative drug or dose PGx Profile (7/6) for moderate risk (12.5%): treat with alternative drug or dose PGx Profile (6/6) for low risk (0%): treat with conventional dose /cder/genomics/BioITFinalII.pdf FDA修改伊立替康说明书 On July 7, 2005, the FDA approved revisions to the safety labeling for irinotecan HCl injection (Camptosar, made by Pfizer, Inc.) to recommend reduced dosing in patients who are homozygous for the UDP-glucuronosyltransferase 1A1 (UGT1A1)–*28 allele. 20 Century Disgnosis-Directed Therapy One drug one dose for all patients Clinical Diagnosis Concentional Dose Safe/Effective Ineffect/Toxicity Dose Modification /Alternative Drug Safe/Effective 21 Century Genotype-Directed Therapy Right drug dose for right patient Clinical Diagnosisi Durg Choice/Dosage Safe/Effective Genotype Detection New Era of Personalized Therapy Personalized Medicine: tailoring individual drug for each individual patient based on his or her genetic make up 根据个体的遗传结构对每一个体实行量体裁衣的药物治疗 什么是个体化用药？ Clinical Service for Personalized Medicine ? Hunan Consultant Center for Tailored Drug Therapy Mutant Alleles DME Transporters Receptors Large dose Modulation dose Reduce dose or Change drug Clinical Diagnosis Genetic Test for Tailored Drug Center