先灵葆雅公司肿瘤及生物制品部【精选-ppt】

李德岩 博士先灵葆雅公司肿瘤及生物制品部佩乐能： 12KD、 最优化设计的聚乙二醇干扰素 -2b0 24 48 72 96 120 144 168 192 半衰期 3-8小时 (平均 4小时 )1 血清干扰素浓度为零 1 病毒重新出现 2时间时间 (小时小时 )干扰素浓度下降 , HCV RNA滴度升高1. Xu ZX, et al. Hepatology. 1998; 28(suppl): 702A. 2. Lam N, et al. Hepatology. 1997; 26: 22631.干干扰扰素素浓浓度度聚乙二醇化 (PEGylation）的作用 蛋白质药物的 PEG化通过下面三个作用达到延长半衰期的目的：防止肾小球滤过减少免疫原性阻止蛋白酶降解干扰素 的信号传导干扰素应答基因干扰素干扰素受体病毒复制STAT1/2PKR 25 OAS聚乙二醇分子大小对活性的影响5KD12KD30KD20KD体外及体内活性IFN -2bEASL 2001: Schering-Plough Research InstituteSchering-Plough Corporation, Data on fileAdapted from Wyss et al., Current Pharmaceutical Design, 2002PEG分子量逐淅增加半衰期抗病毒活性高 (长 )低 (短 )EASL 2001: Schering-Plough Research InstituteSchering-Plough Corporation, Data on fileAdapted from Wyss et al., Current Pharmaceutical Design, 2002佩乐能（ 12KD）在延长半衰期与 保留抗病毒活性 间取得最佳平衡30KD30KD5KD5KD12KD佩乐能的分子设计原则 延长半衰期，一周一次，避免半衰期过长，体内药物蓄积 最大程度保留生物学活性EASL 2001: Schering-Plough Research InstituteSchering-Plough Corporation, Data on fileAdapted from Wyss et al., Current Pharmaceutical Design, 2002佩乐能 : 聚乙二醇甘乐能12 KD甘乐能 (Intron)(干扰素 -2b)佩乐能 (Peg-Intron)(聚乙二醇干扰素 -2b)佩乐能保留 30%肾脏清除率Stokes 分子半径 (Angstroms)相对清除率(%)02040608010010 30 80 100PEG 5KDPEG 12KD(PEG-IFN -2b,佩乐能 )PEG 20KDWyss et al., Current Pharmaceutical Design, 2002Xian-Hui He et al., Life Sciences, 1999佩乐能半衰期 40小时佩乐能 甘乐能吸收 t1/2 4.6hr 2.3hr 半衰期 40hr 4hr Vd/F(分布容积 ) 0.99 L/kg 1.4L/kg CL/F (清除率 ) 22.0mL/hr.kg 231.2mL/hr.kg 佩乐能 1.5 g/kg持续作用 168小时，一周一次 佩乐能佩乐能 1.5 g/kg小小 时时浓度浓度干扰素干扰素a-2b (pg/mL)0 20 40 60 80 100 1201101001000甘乐能甘乐能 3 MU140 160 180EASL 2001: Schering-Plough Research Institute, Data on File第 168小时血清佩乐能的浓度仍高于甘乐能的峰浓度周一 周二 周三 周四 周五 周六 周日PEG干扰素 -2b与 -2a比较PEG干扰素 -2b PEG干扰素 -2a给药方式 按体重个体化给药 单一固定剂量给药剂量 1.5 g/kg 180 gFDA批准时间 2001年 1月 2002年 12月病人数（ 2002年） 300,000 ?佩乐能的药代动力学特性总结佩乐能 聚乙二醇 -2a干扰素类型 -2b -2a聚乙二醇分子量 12kD 40kD半衰期 40 h 80 h48周时的谷浓度 320 pg/ml 16,000pg/ml肾脏清除率 30% 无完全清除时间 10-14天 28-56天比活性 9107/mg 9106/mg抗病毒活性 28%甘乐能 1%或 7%罗荛愫Glue P, et al. Clin Pharmacol Ther 2000; 68:556. Harris JM, et al. Clin Pharmacokinet 2001; 40: 539. Midi, et alHepatology 2002; 36: 371. PegasysTM (peginterferon -2a). Product information.Nutley, NJ: Hoffmann-La Roche Inc 2002. PEG-IntronTM (peginterferon -2b). Product information. Kenilworth, NJ: Schering Corporation 2001. * personal communication, L Blatt (February 2003) and calculated in CPE assay using A549 cells and VSV.PEG-IFN -2b 药代学Median 500 pg/mlPEG-IFN -2a药代学Median 7000 pg/ml结 论 佩乐能是 12KD聚乙二醇干扰素 -2b 最优化分子设计：延长半衰期的同时，最大程度地保留抗病毒活性 半衰期 40小时 28%甘乐能活性 一周一次，给药方便谢 谢 !jCV5oI!auN(gzT2lFY8rK&dwQ+jCV5oI!auN)gzT2lFY8rK&dxQ+jCV5oI!auN)gzT2lFY8rK&dxQ+jCW5oI!auN)gzT2mFY8rK&dxQ+jCW5oI!buN)gzT2mFY8rL&dxQ+jCW5oI!buN)gzT2mFY8rL&dxQ0jCW5oI!buN)gAT2mFY8rL&dxQ0jCW5pI!buN)gAT2mFZ8rL&dxQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jDW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI$buO)gAT3mFZ8sL&exQ0jDW5pI$buO)gAT3mFZ8sL&exR0jDW5pI$buO)hAT3mFZ8sL&exR0jDW6pI$buO)hAT3mGZ8sL&exR0jDW6pI$bvO)hAT3mGZ8sL*exR0jDW6pI$bvO)hAT3mGZ8sL*exR0kDW6pI$bvO)hAU3mGZ8sL*exR0kDW6pJ$bvO)hAU3mGZ9sL*exR0kDW6pJ$bvO)hAU3mGZ9sL*eyR0kDW6pJ$bvO-hAU3mGZ9sL*eyR0kDX6pJ$bvO-hAU3nGZ9sL*eyR0kDX6pJ$cvO-hAU3nGZ9sM*eyR0kDX6pJ$cvO-hAU3nGZ9sM*eyR1kDX6pJ$cvO-hBU3nGZ9sM*eyR1kDX6qJ$cvO-hBU3nG#9sM*eyR1kDX6qJ$cvO-hBU3nG#9sM*fyR1kDX6qJ$cvP-hBU3nG#9sJ$bvO-hAU3mGZ9sL*eyR0kDW6pJ$bvO-hAU3nGZ9sL*eyR0kDX6pJ$bvO-hAU3nGZ9sM*eyR0kDX6pJ$cvO-hAU3nGZ9sM*eyR0kDX6pJ$cvO-hBU3nGZ9sM*eyR1kDX6pJ$cvO-hBU3nG#9sM*eyR1kDX6qJ$cvO-hBU3nG#9sM*fyR1kDX6qJ$cvP-hBU3nG#9sM*fyR1kDX6qJ$cvP-hBU4nG#9sM*fyR1kEX6qJ$cvP-hBU4nG#9tM*fyR1kEX6qJ%cvP-hBU4nG#9tM*fyR1kEX6qJ%cvP-iBU4nG#9tM*fyS1kEX6qJ%cvP-iBU4nH#9tM*fyS1kEX7qJ%cvP-iBU4nH#9tM(fyS1kEX7qJ#9sM*eyR1kDX6qJ$cvP-hBU3nG#9sM*fyR1kDX6qJ$cvP-hBU3nG#9sM*fyR1kEX6qJ$cvP-hBU4nG#9sM*fyR1kEX6qJ%cvP-hBU4nG#9tM*fyR1kEX6qJ%cvP-hBU4nG#9tM*fyS1kEX6qJ%cvP-iBU4nG#9tM*fyS1kEX7qJ%cvP-iBU4nH#9tM*fyS1kEX7qJ%cwP-iBU4nH#9tM(fyS1kEX7qJ%cwP-iBU4nH#9tM(fyS1lEX7qJ%cwP-iBV4nH#9tM(fyS1lEX7qK%cwP-iBV4nH#atM(fyS1lEX7qK%cwP-iBV4nH#atM(fzS1lEX7qK%cwP+iBV4nH#atM(fzS1lEY7qK%cwP+iBV4oH#atM(fzS1lEY7qK%dwP+iBV4oH#atN(fzS1lEY7qK%dwP+iBV4oH#atN(fzS2lEY7qK%dwP+iCV4oH#atN(fzS2lEY7rK%dwP+iCV4oH!atN(fzS2lEY7rK%dwP+iCV4oH!atN(gzS2lEY7rK%dwQ+iCV4oH!atN(gzS2lFY7rK%dtM(fzS1lEX7qK%cwP+iBV4oH#atM(fzS1lEY7qK%cwP+iBV4oH#atN(fzS1lEY7qK%dwP+iBV4oH#atN(fzS1lEY7qK%dwP+iCV4oH#atN(fzS2lEY7qK%dwP+iCV4oH!atN(fzS2lEY7rK%dwP+iCV4oH!atN(fzS2lEY7rK%dwQ+iCV4oH!atN(gzS2lEY7rK%dwQ+iCV5oH!atN(gzS2lFY7rK%dwQ+iCV5oH!auN(gzS2lFY7rK&dwQ+iCV5oH!auN(gzS2lFY7rK&dwQ+jCV5oH!auN(gzT2lFV4oH#atN(fzS2lEY7qK%dwP+iCV4oH#atN(fzS2lEY7rK%dwP+iCV4oH!atN(fzS2lEY7rK%dwP+iCV4oH!atN(gzS2lEY7rK%dwQ+iCV4oH!atN(gzS2lFY7rK%dwQ+iCV5oH!atN(gzS2lFY7rK&dwQ+iCV5oH!auN(gzS2lFY7rK&dwQ+iCV5oH!auN(gzT2lFY7rK&dwQ+jCV5oH!auN(gzT2lFY8rK&dwQ+jCV5oI!auN(gzT2lFY8rK&dxQ+jCV5oI!auN)gzT2lFY8rK&dxQ+jCV5oI!auN)gzT2mFY8rK&dxQ+jCW5oI!auN%dwQ+iCV5oH!atN(gzS2lFY7rK%dwQ+iCV5oH!auN(gzS2lFY7rK&dwQ+iCV5oH!auN(gzS2lFY7rK&dwQ+jCV5oH!auN(gzT2lFY7rK&dwQ+jCV5oI!auN(gzT2lFY8rK&dwQ+jCV5oI!auN)gzT2lFY8rK&dxQ+jCV5oI!auN)gzT2lFY8rK&dxQ+jCW5oI!auN)gzT2mFY8rK&dxQ+jCW5oI!buN)gzT2mFY8rL&dxQ+jCW5oI!buN)gzT2mFY8rL&dxQ0jCW5oI!buN)gAT2mFY8rL&dxQ0jCW5pI!buN)gAT2mFZ8rL&dxQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jDW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI$buK&dxQ+jCW5oI!auN)gzT2mFY8rL&dxQ+jCW5oI!buN)gzT2mFY8rL&dxQ+jCW5oI!buN)gAT2mFY8rL&dxQ0jCW5oI!buN)gAT2mFZ8rL&dxQ0jCW5pI!buN)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI!buO)gAT3mFZ8sL&exQ0jDW5pI$buO)gAT3mFZ8sI!buN)gzT2mFY8rL&dxQ+jCW5oI!buN)gzT2mFY8rL&dxQ0jCW5oI!buN)gAT2mFY8rL&dxQ0jCW5pI!buN)gAT2mFZ8rL&dxQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jDW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI$buO)gAT3mFZ8sL&exQ0jDW5pI$buO)gAT3mFZ8sL&exR0jDW5pI$8rL&dxQ+jCW5oI!buN)gAT2mFY8rL&dxQ0jCW5oI!buN)gAT2mFZ8rL&dxQ0jCW5pI!buN)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI!buO)gAT3mFZ8sL&exQ0jDW5pI$buO)gAT3mFZ8sL&exQ0jDW5pI$buO)hAT3mFZ8sL&exR0jDT2mFY8rL&dxQ0jCW5oI!buN)gAT2mFY8rL&dxQ0jCW5pI!buN)gAT2mFZ8rL&dxQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jDW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI$buO)gAT3mFZ8sL&exQ0jDW5pI$buO)hAT3mFZ8sL&exR0jDW5pI$buO)hAT3mFZ8sL&exR0jDW6pI$buO)hAT3mGZ8sL&exR0jDW6pI$bvO)hAT3mGZ8pI!buN)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT2mFZ8rL&exQ0jCW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI!buO)gAT3mFZ8sL&exQ0jDW5pI$buO)gAT3mFZ8sL&exR0jDW5pI$buO)hAT3mFZ8sL&exR0jDW5pI$buO)hAT3mGZ8sL&exR0jDW6pI$buO)hAT3mGZ8sL*exR0jDW6pI$bvO)hAT3mGZ8sL*exR0jDW6pI$bvO)hAU3mGZ8sL*exR0kDW6pI$bvO)exQ0jDW5pI!buO)gAT3mFZ8rL&exQ0jDW5pI$buO)gAT3mFZ8sL&exQ0jDW5pI$buO)hAT3mFZ8sL&exR0jDW5pI$buO)hAT3mFZ8sL&exR0jDW6pI$buO)hAT3mGZ8sL&exR0jDW6pI$bvO)hAT3mGZ8sL*exR0jDW6pI$bvO)hAT3mGZ8sL*exR0kDW6pI$bvO)hAU3mGZ8sL*exR0kDW6pJ$bvO)hAU3mGZ9sL*exR0kDW6pJ$bvO-hAU3mGZ9sL*eyR0kDW6pJ$bvO-hAU3mGZ9sL*eyR0kDX6pJ$bvO-hAU3nGW5pI$buO)hAT3mGZ8sL&exR0jDW6pI$buO)hAT3mGZ8sL*exR0jDW6pI$bvO)hAT3mGZ8sL*exR0jDW6pI