艾塞那肽临床药理学与临床应用.ppt

,*,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,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,*,黄仲义简历,1936,年生，,1957,年毕业于复旦大学药学院（原上海医科大学药学院）。五十余年从事于医院药学与临床工作，现任上海市静安区中心医院临床药学与临床药理科终身名誉主任，上海市静安区中心医院国家药品临床研究机构办公室主任。上海复旦大学药学院客座教授，天津医科大学药学院客座教授，世界华人药师临床药学专题研讨会主席，上海药学会医院药学专业委员会顾问，上海药学会药物治疗专业委员会副主任委员，,中国新药与临床杂志,副主编，,中国药房,杂志主编，,中国药师,副主编，,长江流域医院用药分析系统,主编，以及其它多家杂志编委。五十余年来，在医院药学及临床药学积累了丰富经验。在国内首创了静脉配置中心及单剂量作业等新型调剂形式并创建无菌调剂新概念。在抗生素的合理应用及临床药代动力学有很深的造诣。,90,年代初就享受国务院特殊津贴，曾获上海市科技进步奖及上海市劳动模范等光荣称号。参与,临床药理学,教材的编著，并主编,中国非处方药选用指南,一书。从,80,年初至今发表论文一百余篇，,2001,至今发表论文二十余篇。,家庭用药,杂志的“黄药师锦囊”专栏作家。,主要内容,血糖控制,艾塞那肽发展简史,艾塞那肽药效学,艾塞那肽药动学,艾塞那肽药物相互作用,艾塞那肽临床应用,血糖控制,2,型糖尿病病理过程,2,型糖尿病患者，葡萄糖进出血液循环的生理平衡失控导致高血糖。这种平衡是指血糖浓度过高增加给,细胞工作量与,细胞对增加需求作出反应能力之间的平衡。,艾塞那肽发展简史,艾塞那肽药效学,艾塞那肽的主要临床试验,2993-112(30,周,),：艾塞那肽二甲双胍,2993-113(30,周,),：艾塞那肽磺脲类,AMIGO*,2993-115(30,周,),：艾塞那肽二甲双胍磺脲类,2993-112E(52,周,),2993-113E(52,周,)2993-117 2993-119(2,年、,3,年,),2993-115E(52,周,),（开放标签延伸试验）,GWAA,：艾塞那肽,vs,甘精胰岛素（与二甲双胍,及,磺脲类合用）,平行试验,GWAO,：艾塞那肽,vs,甘精胰岛素（与二甲双胍,或,磺脲类合用）,交叉试验,GWAD,：艾塞那肽,vs,预混门冬胰岛素（与二甲双胍及磺脲类合用）,艾塞那,vs,西他列汀作用机制研究,GWBA,：亚洲人艾塞那肽二甲双胍磺脲类,*AMIGO:,AC2993 Diabetes Management for Improving Glucose Outcomes,交叉设计的艾塞那肽和甘精胰岛素对照试验,治疗周数,1,MET,or SFU,艾塞那肽,10,m,g(BID),甘精胰岛素,(QD),筛查,随机,交叉,治疗阶段,I,治疗阶段,II,0,-2,16,32,SFU,或,MET,SFU or MET,艾塞那肽,10,m,g(BID),甘精胰岛素,(QD),患者,:MET,或,SFU,HbA,1c,7.1%,及,11.0%,Patients were treated with 5 g exenatide BID for the first 4 weeks and then 10 g exenatide BID thereafter;Insulin glargine was titrated targeting a fasting glucose 5.6 mmol/L.Mean endpoint insulin glargine dose:Treatment Period 1,28.6 16.8 IU/day(n=69);Treatment Period 2,25.7 17.6 IU/day(n=57).,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,艾塞那肽,/,甘精胰岛素对比试验,:,患者基线特征,艾塞那肽,/,甘精胰岛素,(n=68),甘精胰岛素,/,艾塞那肽,(n=70),总数,(N=138),HbA,1c,(%),8.89 0.13,9.00 0.13,8.95 0.09,空腹血糖,(mmol/L),11.8 0.4,12.2 0.4,12.0 0.3,糖尿病病程,(,年,),6.6 0.6,8.3 0.7,7.4 0.4,年龄,(,岁,),54.5 1.1,55.3 1.2,54.9 0.8,性别,男性,(%),48.5,45.7,47.1,体重,(kg),85.6 2.0,84.0 2.0,84.8 1.4,BMI(kg/m,2,),31.3 0.5,30.9 0.5,31.1 0.4,口服降糖药,(%),二甲双胍,磺脲类,55.9,44.1,54.3,45.7,55.1,44.9,Intent-to-treat sample,N=138;mean SEM or%.,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,艾塞那肽,/,甘精胰岛素对比试验,:,终点时,HbA,1c,变化,-1.8,-1.6,-1.4,-1.2,-1.0,-0.8,-0.6,-0.4,-0.2,0,MET,SFU,in HbA,1c,变化,(%),艾塞那肽,(n=136),甘精胰岛素,(n=127),Intent-to-treat sample,N=138;LS mean SEM.,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,-1.43,-1.39,-1.27,-1.34,0,5,10,15,20,25,30,35,40,45,7.0%HbA,1c,6.5%HbA,1c,患者百分比,艾塞那肽,(n=136),甘精胰岛素,(n=127),艾塞那肽,/,甘精胰岛素对比试验,:,终点时,HbA,1c,达标患者百分比,Intent-to-treat sample,N=138,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,40,38,14,22,艾塞那肽,/,甘精胰岛素对比试验,:,餐后,2,小时血糖波动,-0.5,0,0.5,1.0,1.5,2.0,2.5,3.0,早晨,中午,晚上,*,*,*,餐后血糖波动,(mmol/L),艾塞那肽,(n=136),甘精胰岛素,(n=127),Intent-to-treat sample,N=138;LS mean SEM;*p.001,exenatide versus insulin glargine;*p=.016,exenatide versus insulin glargine.,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,艾塞那肽,/,甘精胰岛素对比试验,:,治疗期间的体重变化,甘精胰岛素,艾塞那肽,时间,(,周,),0,2,4,6,8,12,16,18,20,22,24,28,32,体重变化,(kg),-,3,-,2,-,1,0,1,2,N=138;Intent-to-treat sample,LS mean SEM.,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,n=70,n=68,Data on file,Amylin Pharmaceuticals,Inc.and Lilly USA,LLC.,艾塞那肽和甘精胰岛素相比：,HbA1c,及体重变化,-5,-4,-3,-2,-1,0,1,2,3,11%,3%,24%,63%,百泌达,(n=231),甘精胰岛素,(n=245),5%,10%,63%,23%,和基线相比体重变化,(,磅,),和基线相比,HbA1c(%),变化,See accompanying Prescribing Information and safety information included in this presentation,-35,-25,-15,-5,5,15,25,35,艾塞那肽,/,甘精胰岛素对比试验,:5%,的患者出现的不良反应,TEAE,甘精胰岛素,N=127,n(%),艾塞那肽,N=136,n(%),恶心,4(3.1),58(42.6),头痛,12(9.4),17(12.5),呕吐,4(3.1),13(9.6),咳嗽,11(8.7),6(4.4),感冒,15(11.8),11(8.1),咽炎,10(7.9),4(2.9),头晕,7(5.5),9(6.6),Intent-to-treat sample,N=138;TEAE=treatment-emergent adverse event;Hypoglycaemic events were analysed separately.,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,Data on File,Eli Lilly and Company.,艾塞那肽,/,甘精胰岛素对比试验,:,低血糖发生率,艾塞那肽,(n=136),甘精胰岛素,(n=127),低血糖发生率,(%),0,5,10,15,20,25,30,35,40,所有患者,用二甲双胍,治疗的患者,用磺脲类药物,治疗的患者,*,Intent-to-treat sample,N=138;LS mean(SEM);*p=0.010,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,25.2,14.7,2.6,17.4,34.5,30.0,艾塞那肽,/,甘精胰岛素对比试验,:,总的低血糖发生比率,0,1,2,3,4,5,6,*,*,所有患者,二甲双胍治疗的患者,磺脲类治疗的患者,总的低血糖发生比率,(,次,/,人,-,年,),艾塞那肽,(n=136),甘精胰岛素,(n=127),Intent-to-treat sample,N=138;Incidence densities(number of episodes/exposure)95%CI.,*p=.039,exenatide versus insulin glargine;*p.001,exenatide+metformin versus insulin glargine+metformin.,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,艾塞那肽,/,甘精胰岛素对比试验,:,夜间低血糖发生比率,0,0.5,1,1.5,2,2.5,夜间低血糖发生比率,(,次,/,人,-,年,),*,*,磺脲类治疗的患者,二甲双胍治疗的患者,所有患者,艾塞那肽,(n=136),甘精胰岛素,(n=127),Intent-to-treat sample,N=138;Incidence densities(number of episodes/exposure)95%CI,.,*p.001,exenatide versus insulin glargine;*p=.002,exenatide+metformin versus insulin glargine+metformin.,Barnett AH,et al.,Clin Ther.,2007;29:2333-2348.,艾塞那肽,/,双相门冬胰岛素对比试验,随机,筛查,(HbA,1c,7.0%to 11.0%;BMI,25,及,40 kg/m,2,),时间,(,周,),艾塞那肽,5 g,BID+MET/SFU,当前的,MET/SFU,治疗,预混胰岛素,BID+MET,加,SFU,(,胰岛素治疗目标,FPG 7 mmol/L,及,PPG 10 mmol/L,，每日监测血糖,),-2,-1,0,2,4,8,12,28,52,16,40,艾塞那肽,10 g BID+MET plus SFU,Premixed insulin in this study refers to biphasic insulin aspart(30%rapid-acting insulin aspart);,Mean dose of premixed insulin increased from 15.7 U/d(week 2)to 24.4 U/d(week 52).,Nauck MA,et al.,Diabetologia.,2007;50:259-267.,主要假设,:,在二甲双胍加磺脲类药物治疗不达标的,2,型糖尿病患者加用艾塞那肽血糖控制不劣于预混胰岛素,两种治疗疗效差别均数的,95%,可信区间上限小于,0.4%,，则认为非劣效,艾塞那肽,/,双相门冬胰岛素对比试验,:,患者基线特征,10.0(6.2),9.8(6.3),糖尿病病程,年,8.6(1.1),8.6(1.0),HbA,1c,%,11.3(2.8),11.0(2.7),空腹血糖,mmol/L,30.2(4.2),30.6(4.0),BMI,kg/m,2,83.4(15.6),85.5(15.7),体重,kg,49,53,性别,男性,%,58(9),59(9),年龄,岁,预混胰岛素,艾塞那肽,ITT sample,mean(SD)shown.,Nauck MA,et al.,Diabetologia,.2007;50:259-267.,艾塞那肽,/,双相门冬胰岛素对比试验,:,终点时,HbA,1c,变化,HbA,1c,7%,治疗达标患者,(%),*,32%,24%,0,5,10,15,20,25,30,35,艾塞那肽,预混胰岛素,HbA,1c,变化,(%),-1.04%,-0.89%,-2.0,-1.5,-1.0,-0.5,0.0,ITT sample;left panel;ITT sample,mean change SE shown;NSD=nonsignificant differences;,Right panel:between-group difference*p=.038,Nauck MA,et al.,Diabetologia,.2007;50:259-267.,-0.15%(95%CI,-0.32 to 0.01,p=.067),艾塞那肽,/,双相门冬胰岛素对比试验,:7,点自我血糖监测谱,血糖,(mmol/L),*,*,*,早餐前,早餐后,晚餐前,午餐后,晚餐前,午餐后,03:00,7,8,9,10,11,12,13,艾塞那肽,0,周,艾塞那肽,52,周,7,8,9,10,11,12,13,预混胰岛素,0,周,预混胰岛素,52,周,早餐前,早餐后,午餐前,午餐后,晚餐前,午餐后,03:00,ITT sample,mean(SE)shown;significantly lower mean glucose level observed for exenatide*p.001,premixed insulin*p=.0370;p=.0040;p=.002.,Nauck MA,et al.,Diabetologia,.2007;50:259-267.Copyright 2007 Springer-Verlag.Reprinted with permission from Springer-Verlag.,艾塞那肽,/,双相门冬胰岛素对比试验,:,体重变化,时间,(,周,),体重变化,(kg),5.4 kg,*,*,0,2,4,8,12,16,28,40,52,-3,-2,-1,0,1,2,3,*,*,*,*,*,*,艾塞那肽,预混胰岛素,ITT sample,mean(SE)shown.,p.001,exenatide versus premixed insulin at postbaseline time points.,Nauck MA,et al.,Diabetologia.,2007;50:259-267.Copyright,2007 Springer-Verlag.Reprinted with permission from Springer-Verlag,.,+2.9 kg,-2.5 kg,比较研究总结：艾塞那肽和胰岛素血糖改善作用相似,与甘精胰岛素头对头对照试验：艾塞那肽能达到相似的血糖控制,艾塞那肽减轻体重,甘精胰岛素增加体重,艾塞那肽能提供更严格的餐后血糖控制，甘精胰岛素降低更多空腹血糖,与门冬胰岛素头对头对照试验：艾塞那肽能达到相似的血糖控制,艾塞那肽减轻体重,预混胰岛素增加体重,对于空腹血糖作用相似,艾塞那肽更好地控制餐后血糖，更多患者达到,HbA,1c,7.0%,艾塞那肽,与,西他列汀,对餐后血糖、胰岛素及胰高糖素分泌、胃排空及热量摄入的影响：一项随机、交叉研究,Ralph A.DeFronzo,1,;Ted Okerson,2,;Prabhakar Viswanathan,2,;Xuesong Guan,2,;John H.Holcombe,3,;Leigh MacConell,2,1,Division of Diabetes,University of Texas Health Science Center,San Antonio,TX,USA;,2,Amylin Pharmaceuticals,Inc.,San Diego,CA,USA;,3,Eli Lilly and Company,Indianapolis,IN,USA,艾塞那肽对西他列汀作用机制研究,:,试验设计,主要目的,:,比较艾塞那肽和西他列汀对,2,型糖尿病患者餐后,2,小时血糖的影响,（单用二甲双胍的患者）,MET background;,MOA,mechanism of action;QAM,once per day in the morning,DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.,研究结束,交叉,治疗期,1,治疗期,2,随机化,安慰剂导入,艾塞那肽,5,g,BID,艾塞那肽,10,g,BID,艾塞那肽,5,g,BID,艾塞那肽,10,g,BID,标准餐,标准餐,标准餐,1,周,2,周,2,周,西他列汀,100 mg QAM,西他列汀,100 mg QAM,顺序,A,顺序,B,患者基线特征,有效受试者,(n=61),性别,女性,/,男性,(%),54/46,年龄,(,岁,),54 9,种族,白种人,/,黑人,/,西班牙裔,(%),30/8/62,身高,(cm),167.0 9.9,体重,(kg),91.5 18.8,BMI(kg/m,2,),32.6 5.1,A1C(%),8.5 1.2,糖尿病病程,(,年,),7 5,空腹甘油三脂,(mg/dL),166 93,FPG(mg/dL),178 48,2-hr PPG(mg/dL),245 65,Patients with T2D;MET background;Mean SD,unless otherwise indicated;BMI indicates body mass index,DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.,血浆,GLP-1,血浆艾塞那肽,餐后血浆艾塞那肽浓度超过生理浓度的,GLP-1,Patients with T2D;Evaluable population,n=61 for all treatment groups;Mean SE;2-wk posttreatment concentration data,Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.,Baseline,Exenatide,Sitagliptin,餐后,2,小时血浆,GLP-1(pM),餐后,2,小时血浆艾塞那肽,(pM),0,25,50,75,0,25,50,75,7.2,7.9,15.1,63.8,餐后血糖,(mg/dL),时间,(,分,),标准餐,艾塞那肽降低餐后血糖的程度较西他列汀更大,Patients with T2D;Evaluable population,n=61 for all treatment groups;Mean SE;*LS mean SE,P,0.0001,Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.;Data on file,Amylin Pharmaceuticals,Inc.,基线,艾塞那肽,西他列汀,主要终点,-30,0,30,60,90,120,150,180,210,240,120,160,200,240,280,*,2-hr PPG(mg/dL),阶段,1,终点,阶段,2,终点,After Period 1,patients were switched to the other therapy;Patients with T2D;Evaluable population:exenatide-sitagliptin,n=29;sitagliptin-exenatide,n=32;Mean SE,Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.;Data on file,Amylin Pharmaceuticals,Inc.,艾塞那肽降低餐后,2,小时血糖的程度较西他列汀更大,艾塞那肽,西他列汀,基线,110,130,150,170,190,210,230,250,270,艾塞那肽和西他列汀降低空腹血糖的程度相似,空腹血糖较基线值的改变,(mg/dL),1,Patients with T2D;Evaluable population,n=61 for both treatment groups;LS mean SE;,P,=0.3234,1.Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.;2.Data on file,Amylin Pharmaceuticals,Inc.,基线,FPG,2,:178 mg/dL,艾塞那肽,西他列汀,NS,-19,-15,-25,-20,-15,-10,-5,0,-19,-15,艾塞那肽较西他列汀更大程度地改善胰岛素分泌指数,胰岛素分泌指数,1,艾塞那肽,西他列汀,Patients with T2D;Evaluable population,n=61 for both treatment groups;Geometric LS mean SE,Standard meals administered at t=0 min,1.Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.;2.Data on file,Amylin Pharmaceuticals,Inc.,基线时胰岛素分泌指数,几何平均数,2,:0.4,0.55,P,=0.02,0.82,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0.55,0.82,艾塞那肽较西他列汀更好地降低餐后胰高糖素水平,Patients with T2D;Evaluable population,n=61 for all treatment groups;Mean SE,Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.,基线,艾塞那肽,西他列汀,血浆胰高糖素,(pg/mL),时间,(,分,),标准餐,-30,0,30,60,90,120,150,180,210,240,70,80,90,100,110,120,Patients with T2D;Evaluable population,n=61 for all treatment groups;Mean SD;Acetaminophen was administered immediately before the standard meal,Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.,艾塞那肽延缓胃排空，西他列汀无此作用,时间,(,分,),标准餐,Baseline,Exenatide,Sitagliptin,-30,0,30,60,90,120,150,180,210,240,0.0,2.5,5.0,7.5,10.0,12.5,15.0,17.5,20.0,血浆乙酰氨基酚,(ug/ml),艾塞那肽降低平均热量摄入,和基线相比热量摄入变化,(kcal),1,Patients with T2D;Evaluable ad lib cohort,n=25 for both treatment groups;LS mean SE Standard meals administered at t=0 min,1.Adapted from DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.;2.Data on file,Amylin Pharmaceuticals,Inc.,基线平均热量摄入,2,:1071 kcal,艾塞那肽,西他列汀,P,=0.0227,-134,+130,-200,-100,0,100,200,300,-134,+130,-300,艾塞那肽和西他列汀均能被很好地耐受,轻度至中度的恶心和呕吐是最常见的不良事件,恶心,:,艾塞那肽,34%;,西他列汀,12%,呕吐,:,艾塞那肽,24%;,西他列汀,3%,因为不良事件而中途退出的患者,艾塞那肽组,2,名,(,恶心和症状性低血糖,),西他列汀组,1,名,(,头晕,),无严重低血糖事件,Patients with type 2 diabetes;ITT population,N=95;AE indicates adverse event,DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.,艾塞那肽和西他列汀,:,安全性,艾塞那肽对西他列汀作用机制研究,:,总结,艾塞那肽较西他列汀显著降低餐后,2,小时血糖,和西他列汀相比，艾塞那肽能引起,更大幅度的降低,整个餐后时间段的血糖,餐后血糖波动,餐后胰高糖素水平,胰岛素分泌指数的改善,延缓胃排空,减少热量摄入,空腹血糖的变化艾塞那肽和西他列汀相似,艾塞那肽和西他列汀均能被很好地耐受,DeFronzo RA,et al.,Curr Med Res Opin.,2008;24(10)2943-2952.,百泌达,独有的,5,种关键作用机制,靶器官,百泌达的,5,种作用,1-4,百泌达的关键临床效应,4,增强葡萄糖依赖的胰岛素分泌,持续血糖控制,减轻体重,与二甲双胍合用时，低血糖风险低,恢复,1,相胰岛素反应,延缓胃排空,减少食物摄入,*,抑制胰高糖素，降低肝糖输出,When BYETTA is used with an SFU,there is an increased risk of hypoglycaemia,1.Kolterman OG,et al.,J Clin Endocrinol Metab,.2003;88:3082-3089.2.Nielsen LL,et al.,Regul Pept,.2004;117:77-88.3.,Fehse F,et al.,J Clin Endocrinol Metab,.,2005;90:5991-5997.,4.,Blonde L,et al.,Diabetes Obes Metab,.2006;8:436-447,.,See accompanying Prescribing Information and safety information included in this presentation,*,This effect is postulated to be mediated through the central nervous system.,百泌达,：起始方便、治疗简单,首次注射后,百泌达预充笔可在低于,25C,的室温中保存,5 g BID,10 g BID,药效学小结,百必达通过以下作用，降低,2,型糖尿病患者空腹血糖浓度和餐后血糖浓度，从而改善血糖控制。,对,细胞的作用,增加葡萄糖依赖的胰岛素分泌,恢复第,I,时相胰岛素反应,抑制过高的胰岛素分泌,延缓胃排空,减少食物摄取,艾塞那肽药动学（一）,峰效应和持续效应时间,峰效应,剂量,0.1ug/kg,单次或,2,次,/,日餐前连续给药,5,天后，峰效应均在注射后,3hr,出现,II,型糖尿病患者在连续,5,天给药后,I S.AUC,降低,35%(,与安慰剂相比,),空腹血糖也在注射,3-4hr,明显下降达最低点，血清胰岛素水平也在注射后,1-2hr,到高峰,效应持续时间,剂量,0.1ug/kg,早餐前注射,单次或,2,次,/,日连续,5,天给药，效应持续时间均可维持,5hr,空腹血糖下降时间可持续,8hr,Kolterman,et al,J.clin,Endocrial,Matab,.2003 88,（,7,）,3082-3089,艾塞那肽药动学（二）,吸收,生物利用度：动物数据为皮下注射,65-67%,*,，无人类数据,达峰时间与浓度,*,剂量：,10ugII,型糖尿病患者,峰浓：,211pg/ml,达峰时间：,2.1hr,AUC:1036pg.hr/ml,*,Egan et al Am.J,physiol,Endocrial,Metab,284E 1072-1079,*百泌达产品知识,2005,艾塞那肽药动学（三）,分布与代谢,分布,表观分布容积,28.3L,*,Vd,值与剂量、年龄、性别、种族、体表面积等无关,*,代谢：血浆、组织中均有代谢，但量不知,百泌达产品知识,2005,艾塞那肽药动学（四）,排泄与清除半衰期,排泄：肾脏,*,肾清除率,9.1L/hr,，主要经肾小球滤过，由蛋白水解酶降解,肾功能轻至中度不全（,CLcr30-80ml/,分）肾清除率轻度下降无需调整剂量，重度肾功能不全时肾清除率降至,0.9L/hr,肾清除率与剂量、年龄、性别、种族、体表面积无关,清除半衰期,2.4hr,，且与剂量、年龄、性别、种族、体表面积无关,百泌达产品知识,2005,艾塞那肽药物相互作用（一）,由于艾塞那肽延缓胃排空作用，因此对应用其它需快速胃肠道吸收药物艾塞那肽可降低这些药物吸收速度和,/,或吸收量。,对于效应与药物峰浓度相关药物、例如部分抗菌药物和避孕药物，当合用艾塞那肽时应在艾塞那肽注射前一小时服用。,艾塞那肽药物相互作用（二）,与对乙酰氨基酚相互作用,与艾塞那肽给药时间相关性,零时给药,注射后,1hr,给药,注射后,2hr,注射后,4hr,对乙酰氨基酚,AUC,21%,23%,24%,14%,对乙酰氨基酚,Cmax,37%,56%,54%,41%,对乙酰氨基酚,Tmax,（对照值,0.6hr),0.9hr,4.2hr,3.3hr,1.6hr,如在艾塞那肽注射前,1hr,给药则各参数均无变化,艾塞那肽药物相互作用（三）,此外，地高辛、洛伐他丁、赖诺普利、华法令，与艾塞那肽均有潜在的药物相互作用,地高辛：多剂量艾塞那肽与本品合用可使本品,Cmax,17%,，,Tmax,延长,2.5hr,，但,AUC,无改变,洛伐他丁：降低洛伐他丁生物利用度和推迟本品达峰时间,10ug2,次,/,日艾塞那肽可使单剂量洛伐他丁,AUC,下降,40%,，,Cmax,下降,28%,，,Tmax,延长,4hr,，但,30,周临床研究未见血脂出现规律性改变，如二者合用，必要时需增加洛伐他丁剂量与监测血脂值,赖诺普利：艾塞那肽与本品合用时，仅见赖诺普利,Tmax,延长,2,小时，其余参数未见改变，也未见血压变化,华法令：二者合用时患者,INR,值增高，但未见华法令药动与药效参数明显改变，且对华法令二种手映体,R,和,S,均未见显著影响，但临床常见二者合用时出血现象，因此二药联用时应监测,INR,与注意出血现象,艾塞那肽临床应用（一）,FDA,批准适应症,用于二甲双 、磺酰脲类、噻唑烷酮以及二甲双 和磺酰脲类或噻唑烷酮联合治疗血糖控制不佳成人,II,型糖尿病患者,推荐级别成人,IIa,证据级别成人,A,胍,胍,艾塞那肽临床应用（二）,起首剂量,5ug,应用方法：每日二次早餐和晚餐前,1hr,内皮下注射，或一日二次主餐前，但二次注射时间需间隔,6hr,以上,一月后剂量可增加至,10ug,同时,合用艾塞那肽和磺酰脲类时，为避免低血糖不良事件，磺酰脲应减低剂量,不推荐用于严重肾功能不全者（,cl,cr,30ul/,分）,艾塞那肽临床应用（三）,低血糖不良事件,艾塞那肽临床应用（四）,其它不良事件,总结,谢 谢！,