缓释剂型他汀-疗效与安全的平衡ABmeeting课件

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,缓释剂型他汀,疗效与安全的平衡,缓释剂型他汀疗效与安全的平衡,肠腔,门静脉循环,肝脏,系统循环,药物的吸收过程,药物在肠腔,药物,被吸收,药物经过,肝脏首过效应,最后进入,系统循环的药量,80,100,60,20,举例,Birkett DF.Australian Prescriber 1991;14:14-17,他汀类药物肝脏首过效应明显，大多数他汀肝脏首过清除,60%,他汀缓释片的设计：必要性和合理性,肠腔门静脉循环肝脏系统循环药物的吸收过程药物在肠腔药物药物经,肝脏对药物摄取存在饱和效应药代动力学证据,氟伐他汀单次应用剂量从,10mg,到,20mg,，循环药量成比例的增加，,然而剂量超过,20mg,后，循环药量超比例的增加，可能存在肝脏首过饱和性,Appel S Drugs of today 1996;32(Suppl.A):37-55.,给药时间,氟伐他汀血浆浓度,(ng/ml),氟伐他汀,10mg,氟伐他汀,20mg,氟伐他汀,40mg,他汀缓释片的设计：必要性和合理性,肝脏对药物摄取存在饱和效应药代动力学证据氟伐他汀单次应用,0 5 10 20 40 80 (mg),其它他汀同样具有肝脏对药物摄取存在饱和效应,阿托伐他汀剂量超过,20mg,后循环药量不成比例的增加。,AUC(hng/mL),阿托伐他汀,Donald D,et al.Clin Pharmacol Ther 1996;60:687,95,0 5 10 20,肝脏对药物摄取的饱和效应带来的临床问题,他汀大剂量口服后，肝脏药物增加有限,从标准剂量起，他汀剂量每增加一倍（单次服用），,LDL-C,水平约降低,6%,他汀大剂量口服后，循环药物浓度急剧增加，导致不良反应增加,中国成人血脂异常防治指南,.,中华心血管病杂志,2007;35(5):390-413.,Alsheikh-Ali AA et al.J Am Coll Cardiol;50:409-18,10,20,30,40,50,60,LDL-C,降低,%,0,6%,6%,他汀药物,10 mg,20 mg,40 mg,80 mg,6%,他汀缓释片的设计：必要性和合理性,肝脏对药物摄取的饱和效应带来的临床问题他汀大剂量口服后，肝脏,他 汀,肠道吸收迅速,肝脏摄取,单次大剂量给药超过肝脏摄取饱和度,系统暴露,不良反应,Smith HT et al.Am J Hypertens 1993;6:375S-382S,.,Appel-Dingemanse S et al.Presented at:29th European Symposium on Clinical Pharmacy;2000;Basel,Switzerland.,在肠道缓慢吸收,避免肝脏对药物摄取的饱和作用,降脂疗效增加,延长肝脏对药物的接触时间,他汀缓释的意义,他汀缓释片的设计：必要性和合理性,他 汀肠道吸收迅速肝脏摄取单次大剂量给药超过肝脏摄取饱和度,氟伐他汀缓释片的缓释原理,胶体外层逐渐溶解，氟伐他汀透过胶体外层缓慢释放,骨架片,摄入,外层为亲水聚合物,水合后形成胶体层,氟伐他汀缓释片：羟丙基甲基纤维素凝胶骨架片结构,Data on file.Novartis Pharmaceuticals Corporation,.,氟伐他汀缓释片的缓释原理胶体外层逐渐溶解，氟伐他汀透过胶体外,专利释放技术,0,级动力学释放,8,小时,0,0.5,2,4,8,时间（小时）,释放比例（）,Data on file,专利释放技术0级动力学释放8小时00.5248时间（小时）,Barilla D,et al.Biopharm.Drug Dispos.2004;25:51-59,剂量增加到,160mg,仍未出现肝脏饱和效应,口服后时间,Fluvastatin 10mg,Fluvastatin 20mg,Fluvastatin 40mg,速释胶囊,缓释片,氟伐他汀血药浓度,(ng/ml),40mg,剂量下观察到了饱和效应,避免了肝脏对氟伐他汀摄取的饱和效应,Barilla D,et al.Biopharm.Drug,缓释片与速释胶囊药代动力学曲线比较,吸收速率减慢,50%,系统暴露减少,50%,Barilla D,et al.Biopharm.Drug Dispos.2004;25:51-59,速率,：,Cmax/AUC0-t,0.19,vs.,0.37,药量,：,AUC0-t(ng*h/ml),564,vs.,1165,缓释片与速释胶囊药代动力学曲线比较吸收速率减慢系统暴露减少B,平均血药浓度,(ng/ml),0,10,20,30,40,时间（小时）,0,200,400,600,800,1000,1200,氟伐他汀缓释片,80mg,（餐时）,氟伐他汀缓释片,80mg,（餐后,2.5h,）,氟伐他汀速释片,80mg,氟伐他汀缓释片的药代动力学不受食物的影响,Appel-Dingemanse et al.Abstract presented at European Symposium on Clinical Pharmacy Congress,Basel,Switzerland.2000,Data on File.XUO320B Study W 251.Novartis Pharmaceuticals Corporation,平均血药浓度(ng/ml)010203040时间（小时）0,氟伐他汀钠缓释片可以,1,天中任何时间服用,-40,-35,-30,-25,-20,-15,-10,-5,0,早上服用,晚上服用,8,周时血脂较基线变化值,LDL-C,TC,非劣效检验早晨服用与晚上比,P=0.0118,Hubert Scharnagl,et al.Cardiology 2006;106:241248,氟伐他汀钠缓释片可以1天中任何时间服用-40-35-30-2,氟伐他汀钠缓释片的调脂疗效和安全性,氟伐他汀钠缓释片的调脂疗效和安全性,缓释片,III,期试验汇总,双盲、随机、活性药物对照、多中心、平行组研究,共入选,1,674,例原发性高胆固醇血症患者,Ballantyne CM et al.,Clin Ther,2001;23:177192.,缓释片III期试验汇总双盲、随机、活性药物对照、多中心、平行,降脂疗效突破“,6%”,原则,27%,38%,40,35,30,25,20,15,10,5,0,氟伐他汀钠缓释剂,80 mg,日,1,次,氟伐他汀速释胶囊,40 mg,日,1,次,LDL-C,中位降低,(%),氟伐他汀速释胶囊,40 mg bid,38%,11%,Ballantyne CM et al.,Clin Ther,2001;23:177192.,治疗,4,周,降脂疗效突破“6%”原则27%38%403530,治疗,4,周后,40%,的患者,LDL-C,的降幅,40%,Ballantyne et al.Clin Ther 2001;23:17792,应用氟伐他汀钠缓释片,80mg,日,1,次,(n=835),40%,的患者,LDL-C,的降幅,40%,治疗4周后,40%的患者LDL-C的降幅 40%应用氟,升高,HDL-C,幅度，最高达,21%,N=450 272 750 98 64 203 21 15 36,HDL-C,较基线幅度,(%),Ballantyne CM et al.Clin Ther 2001;23:177192.,24,周,*P0.01,+P300,速释胶囊,40mg QN,速释胶囊,40mg BID,氟伐他汀钠缓释片,80mg QN,升高HDL-C幅度，最高达21%N=450 27,降低,TG,幅度，最高达,31%,*,p 0.05 vs,氟伐他汀速释剂,40mg qd,所有患者,200,200299,300,TG24,周时平均改变,(%),基线,TG(mg/dL),10%,17%,24%,19%,16%,26%,22%,19%,17%,24%,31%,12%,35,30,25,20,15,10,5,0,氟伐他汀钠缓释剂,40 qn,氟伐他汀速释剂,40 mg bid,氟伐他汀钠缓释剂,80 mg qd,*,Ballantyne CM et al.Clin Ther 2001;23:177192.,降低TG幅度，最高达31%*p 0.05 vs 氟伐他汀,降低糖尿病病人的小而致密的,LDL,-28%,安慰剂,(n=39),氟伐他汀缓释片,80mg(n=31),ApoB(mg/L),密度,L6,V,300,250,