密固达临床试验介绍课件-PPT【可编辑的PPT】

1、目 录密固达作用机制分子结构决定独特的效果体外研究最强的抗骨吸收作用药理结构特点强大吸附力与抗骨吸收作用密固达与Paget骨病密固达与绝经后骨质疏松 1密固达简介通用名称：唑来膦酸注射液商品名称：密固达（Aclasta）规格:100ml：5mg（以唑来膦酸无水物计）性状:本品为无色的澄明液体2NPOOPOHOHOHOHOHC双膦酸药物不同的 R2 侧链结构利塞膦酸NNPOOPOHOHOHOHHOC唑来膦酸H2NPOOPOHOHOHOHOHC伊班膦酸阿伦膦酸CH3NPOOPOHOHOHOHOHC3唑来膦酸是作用最强的双膦酸盐Green JR, et al. J Bone Miner Res. 1

2、994;9:745-751.高钙血症小鼠体内相对抑制强度体外相对抑制强度，骨培养100101102103104105106100101102103唑来膦酸利塞膦酸盐伊班膦酸盐阿仑膦酸盐奥帕膦酸盐帕米膦酸Neridronate氯屈膦酸盐羟乙双膦酸盐R = 0.97动物研究证实：唑来膦酸的骨吸收抑制强度是帕米膦酸盐的100-850倍4高吸附力的双膦酸药物在骨组织中很少弥散，停留在骨表面附近BPBPBPBP通过循环强大的再吸附作用BP低脱离BP迅速吸收G Russell 2005注射后几个月内组织液中仍可检测到双膦酸类药物唑来膦酸与骨矿盐的强大结合力:HONNOO=PPOHOHOHOH唑来膦酸具有更

3、长的作用周期唑来膦酸在骨组织循环的可能机制5Sham OVXalendronate 200 g/kgZOL 0.8 g/kgZOL 4.0 g/kg 近端胫骨干骺端pQCT Gasser JA, Green J. Bone. 2002;30(3):41S.松质骨 BMD (%)周6040200048121620242832OVX + 1 x ZOL IVZOL 20 g/kg成人唑来膦酸5mg的等效剂量ZOL 100 g/kgZOL 500 g/kg唑来膦酸单次静脉给药对于去卵巢大鼠的长期抗骨吸收作用6 去卵巢大鼠治疗32周后近端胫骨干骺端Micro-CT图像Gasser JA, Green

4、JR. Bone. 2002;30(3):41S.成人唑来膦酸5mg的等效剂量OVX 4 g/kg 20 g/kg100 g/kgSHAM单次静脉注射人类的等效剂量对于骨组织微结构具有保护作用7唑来膦酸防止去卵巢大鼠骨组织结构恶化以及生物力学的降低防止去卵巢导致的以下参数降低: 骨体积分数 1 骨小梁厚度1 骨小梁数量 1 连接的密度 1 承受最大应力 (椎体)1 承受最大压力 (股骨: 3点弯曲试验 )2能量吸收2防止去卵巢导致的以下参数增加: 骨小梁间隙 1 结构模型参数 11. Glatt M, et al. Osteoporos Int. 2004;15:707-715.2. Horn

5、by SB, et al. Calcif Tissue Int. 2003;72:519-527.81. Green JR, et al. J Bone Miner Res. 1994;9:745-751. 2. Data on file, Novartis.体外颅骨测量：抑制重吸收 vs 矿化作用治疗比抑制矿化抑制骨吸收化合物400200.05阿伦膦酸IC50 (M) 2IC50 (M)1500帕米膦酸1000.215,0000.00230唑来膦酸 0.4氯屈膦酸 50125利塞膦酸0.0160060.02伊班膦酸40084.0依替膦酸102.5唑来膦酸抑制骨吸收与矿化作用具有更高的治疗比9

6、唑来膦酸在Pagets骨病的应用* HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly).Reid IR, et al. N Engl J Med. 2005;353:898-908.HORIZON*ts骨病临床研究: 疗效终点患者总数: N = 357主要终点: 治疗反应 过高的SAP水平降低 75%或治疗6个月SAP水平达到正常的百分比 次要终点：治疗28天SAP水平达到正常的百分比产生治疗反应的时间骨吸收指标的变化血浆 CTX尿 CTX11 2 个月1Zoledronic Acid

7、(n = 176)% 产生治疗反应的患者百分比* 6 个月290639689%, P .001%, P .001反应患者 碱性磷酸酶正常患者% 产生治疗反应的患者百分比*产生治疗反应: 过高的SAP水平降低75%.Dosage: RIS: 60 days: 1 x 30 mg/day; Zoledronic Acid: single infusion of 5 mg. 1. Lyles K, et al. Poster presented at ECCEO5; March 16-19, 2005; Rome, Italy. 2. Reid IR, et al. N Engl J Med. 20

8、05;353:898-908.治疗2个月和6个月时唑来膦酸具有比利塞膦酸更好的临床疗效Risedronate (n = 171)47267458Zoledronic Acid(n = 176)Risedronate (n = 171)12天数010203040506070809010010286391182*7% 碱性磷酸酶水平正常患者百分比 (%) *P .001.唑来膦酸与利塞膦酸治疗：碱性磷酸酶正常化疗效比较Zoledronic Acid (n = 176)Risedronate (n = 171)Reid IR, et al. N Engl J Med. 2005;353:898-90

9、8.1%*63%*76%*89%26%49%58%13*P .001010286391182天数0100200300400500全血碱性磷酸酶水平 (U/L)*随访时平均血浆碱性磷酸酶水平( SE) 唑来膦酸 (n = 176)利塞膦酸 (n = 171)正常范围Reid IR, et al. N Engl J Med. 2005;353:898-908.*P .001*P .001*P .001*P .001唑来膦酸使平均血浆碱性磷酸酶水平恢复正常14HORIZON-PFT (Pivotal Fracture Trial关键部位骨折试验) 2301 研究核心内容密固达与绝经后骨质疏松 全面降

10、低各部位骨折风险,提高骨密度Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture TrialThe NEW ENGLANDJOURNAL of MEDICINEESTABLISHED 1812MAY 3, 2007VOL. 356 NO. 18Once-Yearly Zoledronic Acid for Treatmentof Postmenopausal OsteoporosisDennis M. Black, Ph.D., Pierre D. Delmas, M.D.

11、, Ph.D., Richard Eastell, M.D., Ian R. Reid, M.D.,Steven Boonen, M.D., Ph.D., Jane A. Cauley, Dr.P.H., Felicia Cosman, M.D., Pter Lakatos, M.D., Ph.D.,Ping Chung Leung, M.D., Zulema Man, M.D., Carlos Mautalen, M.D., Peter Mesenbrink, Ph.D., Huilin Hu, Ph.D.,John Caminis, M.D., Karen Tong, B.S., Ther

12、esa Rosario-Jansen, Ph.D., Joel Krasnow, M.D., Trisha F. Hue, M.P.H.,Deborah Sellmeyer, M.D., Erik Fink Eriksen, M.D., D.M.Sc., and Steven R. Cummings, M.D.,for the HORIZON Pivotal Fracture TrialBlack DM, et al. N Engl J Med. 2007;356:1809-1822.16HORIZON Pivotal Fracture TrialHORIZON关键骨折临床研究(PFT) 概述

13、研究目的：观察唑来膦酸5毫克治疗降低绝经后骨质疏松患者骨折风险的疗效为期3年，随机、双盲、安慰剂对照、多中心临床研究27个国家，239各研究中心的7736名女性入组 治疗方法：每年一次静脉输注唑来膦酸5毫克或安慰剂基础补充钙剂 10001500 mg/d; 维生素 D 4001200 IU/d主要疗效终点第I层面：降低3年椎体骨折风险第I和II层面：延长3年发生髋部骨折的时间ZOL = zoledronic acidBlack DM, et al. N Engl J Med. 2007;356:1809-1822.17新发椎体骨折发生率%60%*(43%, 72%)71%*(62%, 78%)

14、010010203年5151.5%(42/2822)3.7%(106/2853)2.2%(63/2822)7.7%(220/2853)3.3%(92/2822)10.9%(310/2853)70%*(62%, 76%)*P .0001, relative risk reduction vs placebo (95% confidence interval) Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.唑来膦酸治疗3年椎体形态骨折发生率降低达70%ZOL 5 mg 安慰剂18唑来膦酸治疗3年多发(2)椎体形态骨折发

15、生率降低达89% 89%*(77%, 95%) 3年多发(2)椎体骨折0.2%(7/2822)2.3%(66/2853)多发(2) 椎体骨折发生率%0213ZOL 5 mg 安慰剂*P = .0001, relative risk reduction vs placebo (95% confidence interval)Data from Black DM, et al. N Engl J Med. 2007;356:1809-1822.19*Relative risk reduction vs placebo (95% confidence interval)Adapted from Bl

16、ack DM, et al. N Engl J Med. 2007;356:1809-1822.P = .00241230Placebo (n = 3861) ZOL 5 mg (n = 3875)首次髋部骨折发生的时间 (月)036912151821242730333641%*(17%, 58%)唑来膦酸治疗3年髋部骨折累积危险性降低达41%累积危险性 (%)20P .0001累积危险性(%)发生第一次临床椎体骨折的时间（月）036912151821242730333677%*(63%, 86%)Placebo (n = 3861) ZOL 5 mg (n = 3875)1230*Relat

17、ive risk reduction vs placebo (95% confidence interval)Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.唑来膦酸治疗3年临床椎体骨折累积危险性降低达77%21P = .0002发生第一次非椎体骨折的时间（月）24681012036912151821242730333625%*(13%, 36%)Placebo (n = 3861) ZOL 5 mg (n = 3875)0*Relative risk reduction vs placebo (95% confid

18、ence interval)Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.唑来膦酸治疗3年非椎体骨折累积危险性降低达25%累积危险性(%)22Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates. *P = .0024; P .0001; P = .0002; relative risk reduction vs placebo Hip fracture was not excluded from an

19、alysis of non-vertebral fracture.Black DM, et al. N Engl J Med. 2007;356:1809-1822.41%*(17%, 58%) 77%(63%, 86%)25%(13%, 36%)临床椎体骨折髋部骨折非椎体骨折1.4%(52/3875)0.5%(19/3875)2.5%(88/3861)2.6%(84/3861)8.0%(292/3875)10.7%(388/3861)3年新发临床骨折累积危险性（%）010515唑来膦酸治疗3年降低临床骨折累积危险性（髋部、椎体、非椎体）ZOL 5 mg Placebo230612182430

20、36月2.00.02.04.06.08.05.90*3.66*2.39*与基线比较变化率 % ZOL 5 mgPlacebo268262236228265258226212ZOL n =PBO n =Bracketed values are least square mean difference, ZOL vs placebo*P .0001, P-value computed from 3-way ANOVA with treatment, stratum and center as explanatory variables.Adapted from Black DM, et al. N

21、 Engl J Med. 2007;356:1809-1822.6.71%*与安慰剂比较唑来膦酸治疗3年显著增加椎体BMD24与安慰剂比较唑来膦酸治疗3年显著增加全髋BMD2.01.00.01.02.03.04.03.05.035153516322830613543354232483077ZOL n =PBO n =Bracketed values are least square mean difference, ZOL vs placebo*P .0001, P-value computed from 3-way ANOVA with treatment, stratum and regi

22、on as explanatory variables.Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.061218243036月2.83*1.93*4.70*ZOL 5 mgPlacebo6.02%*与基线比较变化率 % 25与安慰剂比较唑来膦酸治疗3年显著增加股骨颈BMD061218243036月2.01.00.01.02.03.04.03.05.02.17*1.58*3.89*ZOL 5 mgPlacebo35223522323430673549354832543083ZOL n =PBO n =Bracket

23、ed values are least square mean difference, ZOL vs placebo*P .0001, P-value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables.Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.5.06%*与基线比较变化率 %26PlaceboCT检测骨结构结果显示唑来膦酸治疗后骨小梁结构得到保留Recker R, et al. Presen

24、ted at: 34th European Symposium on Calcified Tissues; May 5-9, 2007;Copenhagen, Denmark. Abstract PO21-M.ZOL 5 mg唑来膦酸与安慰剂组间比较骨小梁体积(BV/TV，16.59% vs,13.52%, P0.015 )骨小梁数量(1.31/mm vs.1.22/mm, P0.006),骨小梁空间(0.76 mm vs.0.82 mm, P0.008),连接的密度(4.32/mm3 vs.3.57/mm3, P0.052).27唑来膦酸静脉给药后3天内出现的常见症状 （5%） 0246810121416给药次数发热肌痛流感样症状头痛关节痛1