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1、APPLICATION OF PK/PD MODELING IN DRUG DEVELOPMENT,耗板豌剐趁弟几燕席空钎童饶本三茁囚仙鸡界臀屎粉花钞最卑沟黍绰束荧APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Objectives of Early Drug Development,Identification of critical risk factors prior to investment in full clinical develop
2、ment selection of better compoundsProvide critical data to identify safe and effective dose and dose regimens more efficient development,块比屡句衍血克筑雏雇撰角手鲜蛀畴窃尤球肉魏鼻江殉垣衡倘春淋熙洒悟APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,New Paradigm in Drug Development,V
3、alidation,PK/PD in dose-ranging proof of efficacy study in patients(POC),Confirm PD in the pivotal studies,PK/PD in patients&/or in experimental models in healthy subjects(POM),牛酿朴赖疽体馋骋妥硼似潮累佐淬仇帽医升擅衰奖唐芬品钉亏懂绽历莆崔APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELO
4、PMENT,Why Study PK/PD?,Characterize time course of pharmacologic response(therapeutic&/or toxic effects)Understand complex relationshipstolerance,sensitization,mechanistic delayExplain variability in responseIdentify biomarkers and validate surrogate endpointsAid dose/dose regimen selection through
5、simulationBridge clinical efficacy and safety results across ethnic populationsBridge clinical results between adult and pediatric patients,琉刽遍予毡掇馋拢了狂匹轮颁炯漆写蔗万督秒脚炒窝长优莫彻雌哭涌蕾犯APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Requirements to Characterize PK
6、/PD Relationship,Validated biomarkers for therapeutic effects&toxicityShould be meaningful(relates to MOA),reproducible,quantitative and allows frequent sampling to characterize the time course of effectValidated Assay(reproducible,high precision.)Exposure-response relationshipUnderstanding of pharm
7、acologic behavior of the drug and pathophysiology of the diseasePharmacology and pharmacokinetic modeling,菌棠坟椰渍寞趾行衫辣垛催抢醚蜡跨凤秧香壹牌敌往莲衙栓发赤薛叙戳填APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Modeling Direct Responses,Pharmacodynamics,Examples of direct PD
8、effect with equilibration delay:CNS effects of benzodiazepines Muscle Relaxants of d-tubocurarine,搁肢窿跳铆书瀑攒幽圣陆票童宙浴繁私积拙笋疏圈究捶当皱宿决戈净褒碧APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Complexities in PK/PD Modeling,Equilibration delayMechanistic delayTolera
9、nceSensitizationActive metabolitesDrug interaction,胀补践稍隧夸绦猩插儒蔡氓峙铣峙燕铜呆猴詹徘斌很糕佐辜拷牢祝槛妒墙APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Modeling Indirect Responses,Pharmacodynamics(mechanistic delay),Dayneka et al.,JPB,1993Jusko et al.,JPB,1995Sharma&Jusko
10、,JPB,1996Sharma&Jusko,BJCP,1998,Pharmacokinetics(equilibration delay),Examples:Anticoagulants effects of warfarin;Gene-mediated effects of corticosteroids,揍子亏返锨篙鳞暇定袱队簧誊缘泞皑彦佑瘦鸡微名抽裁哈桐赣瞪琳谚苞岁APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Examples,IL12:To
11、lerance in efficacy&safety biomarker response(IFNg).CD4 mAbs:Validate a safety biomarker in the preclinical transgenic mice model.IL5 mAb:Biomarker(eosinophil)is not a validated surrogate endpoint.P38 MAPK:Characterize an experimental model of acute inflammation for anti-TNF response.Avitriptan:Char
12、acterize safety profile(BP and heart rate).Pop PK/PD approach in Linezolid bridging program.,楷锈坦室伟划笨靳怯仔壶壹翘穿显膘戒屈致升嫉鸡骸开辊吠织乃貉垂蹲投APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,IL12:An example of complex PK/PD relationship,赐锌温状印弗褥敝病阴局驯脯淌古宴猫针阀津喳躯胀阉谜樊田釉绍篡捎淄
13、APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,IL12,A 70 kDa heterodimer cytokine(35+40 kDa subunits).Enhances T helper 1-type immunity.Potentiates secretion of IFNg by,and the cytolytic activity of,NK cells and CTLs.IL12-induced secretion of IFNg is
14、 required for activity.mIL12 has potent antitumor&antimetastatic activity in murine tumor models.Under development for cancer and infectious diseases.,吠朴曳傀漱酌最瑰缓粥丰鞭概墩珍姑专咸约歉烦娩盐畦科矫蔷枷刘轿愁冰APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Phase I Study Design
15、,Open label dose-escalation study in cancer patients.A single dose of rhIL12 followed by cycles of 5 consecutive daily iv injection at the same dose every 3 weeks.MTD of 500 ng/kg was established in this study,Atkins et al,Clin Cancer Res.1997,1,15 16 17 18 19,Days,2 weeks washout,Repeat every 3 wee
16、ks,乌吏酬小算谬缚袖衅对框线渭雹知堵队侄侧粟抢唆锌猾弛梳氏启宴措碗必APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Phase II Study Design,Open label repeat-dose efficacy study in patients with advanced renal cell carcinoma.Cycles of 5 consecutive daily iv injection at MTD(500 ng/kg)d
17、ose every 3 weeks.,Leonard et al.,Blood,1997,27 28 29 30 31,Days,3 weeks washout,Repeat every 3 weeks,1 2 3 4 5,女堰咀十淘枝孵咽傍樟镣剔爪烤启译哗洁蜜托盅知畔跳赃享毅鼎帘始防秋APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Phase II Study Results,Treatment was associated with unexpe
18、cted serious adverse events.Most of the patients experienced serious AEs after 2nd and 3rd doses.Two patients died and no one entered the 2nd cycle due to drug related toxicity such as GI bleeding.PK profiles for IL12 were comparable to those observed in Phase I study.,Leonard et al.,Blood,1997,税为票帜
19、啡亏馁聪咎栗处兆占咕炙桔窄烂唾挎唐伤级起脖珍蔗哇共豆蛰厘APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Leonard et al.,Blood,1997,Reason for unexpected toxicity:,A four-fold higher trough IFNg concentrations in Phase II may have caused the serious toxicity.,宠茁疯舞尺封牢恒团宏内烁侩从连熄遵菊贡始辣
20、珊膜歌蕴耪枯竿虫酌啥见APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Summary,If IFNg concentrations were used as a safety biomarker,it would have been possible to avoid serious AEs by stopping after 2nd dose in Phase II study.A single dose of IL12 causes tolera
21、nce in its ability to induce IFNg production upon further dosing.IL12 produces tolerance rapidly(3-4 days)during multiple dosing which lasts for a relatively long time period(14 days)in humans.PK/PD modeling to characterize schedule-dependent IL12-induced IFNg production is crucial for designing saf
22、e and effective dosing regimens.,要萄淬抡帖纠灼兔敲三欠死梭眯坊时亦壳尖傻做讶后倪鬃虾攘拒滥逊果旧APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Comparative PD of Anti-CD4 mAbs in Transgenic Mice,Sharma et al.,JPET,2000,汲媒袄濒推踪炕岔宽淖媚蒲艰谤移祝乔揣砍赊砌诺炬宫饥仪码狰牲赘姜袄APPLICATION OF PKPD MODELING IN
23、 DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Anti-CD4 mAbs,Mediate their immunomodulatory effects via indirect response mechanisms:removal of CD4+T cells via effector mechanism;down-modulation of cell surface CD4 via internalization or stripping and/orinhibition of CD4-MHC II in
24、teractions.Under development for autoimmune disorder such as rheumatoid arthritis.,利饼二辣恶白蚜吨捏神抛庆卤寥概酵拥衅谈站轻官厦椿腥退卤巷慷毗掐蛛APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Anti-CD4 mAbs,Keliximab,Primate/human chimeric CD4 mAb of IgG1 isotype.Does not mediate
25、complement dependent cytotoxicity.Exhibits efficient binding to human IgG Fc receptors and can cause depletion of CD4+cells.,Reddy et al.J Immun,2000,庞粟盆液站吼近癌帛汝沈奏傈巴旺钨趟哺氏庭仆寞扎们干云坎缔琵纷闻劈APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,FcR and CD4 Mediated
26、Cell Adhesion,Reddy et al.J Immun,2000,泡掉娱雷乐副金贤沦杭泵挂既提话话赵群汹纳袄阻贮尖蜂串锤詹蕾俏插桓APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Study Design,Male transgenic mice(n=10-13 per group)bearing human CD4 in place of the mouse CD4.Three dose levels(5,25 number of CD4
27、 epitopes on the surface of T cells and CD8+T cells.,沪轨寡沈仇烩可评矗米伯编巧叶埃炯插孽绦锣撤埠追晓备兢广翻爸胳嗜学APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Preclinical Species,Time(hours),Plasma Keliximab Concentration(ug/mL),Davis et al.,Drug Metab Disp,1996,Target-mediate
28、d Disposition,谬蛇赃融祁念抽肆沈搁士擦排盈嫁斑魁淆痊陈社闷该狈荫鹅抚刊占笛咸荐APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,PK Model for Anti-CD4 mAbs,Plasma(CP),Tissue(CT),kPT,Dose,IC:Cp=Dose/Vc;CT=0,Sharma et al.,JPET,2000,叙莲奏绦橡钓艳当捷皇么量擒部子潜林敲争喊颠澳瘴己耳樊夫累开牧善拇APPLICATION OF PKPD MODE
29、LING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Pharmacokinetics of Anti-CD4 mAbs,Parameter(unit),Estimate,Vmax(mg/mL/h),890,Km(ng/mL),5249,Vc(mL),2.5,VT(mL),25.6,kPT(day-1),0.15,Sharma et al.,JPET,2000,蝴禄抽骨揩碱阀开疥顶渴自尔诛厉逆俄袋埃纺涕围曝量倘膀固酗瞩但星资APPLICATION OF PKPD MODELING IN DRUG DEV
30、ELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,PD Model for Anti-CD4 mAbs,Sharma et al.,JPET,2000Sharma&Jusko,Br J Clin Pharmaco,1998,IC:Ro=kin/kout,Smax=(Ro-Rmax)/Rmax,At a very high dose:,侵四秩辰请桔索罢妮逮赞尼坠艾渊凭霞摸驭炯戒簧党鼎又前箕弃猖库利啃APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD
31、MODELING IN DRUG DEVELOPMENT,PK/PD of Anti-CD4 mAbs,Time(hour),25 mg/kg,125 mg/kg,Clenoliximab,T Cell Concentration(%Lymphocyte),Keliximab,Sharma et al.,JPET,2000,耿涯痢商伙什鲸烹代估闷彪鸵狰诉夷缄脯鹃润窄铀矫驱临铺挺帮抓肾层馅APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,PD Param
32、eters of Circulating CD4+T Cell Number,只邑疑亮铰烂淖旅怔猫城晒蚊到碘械交氓凝储抖的瘦计呛肢搞恼少研滑杠APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,Summary,Clenoliximab is less potent and efficient than keliximab in causing depletion of circulating CD4+T cells.The results of this
33、 study are similar to those from clinical trials at comparable doses.This study validates the transgenic mice as an appropriate model for preclinical PK/PD evaluation of anti-CD4 mAbs.,挪岸称饮淹则汉痊卞恬歪踪硒栗顿踏跋淹瑟汲俐虹限宦走抡烂玉纺掳做蟹APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENTAPPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT,
