芮达与速释利培酮的区别.ppt
帕利哌酮缓释片与速释利培酮异同,1,武汉大学人民医院 徐顺生,内部资料 严禁翻印及传播,2,若干基础和临床研究发现两者存在许多不同之处,3,两种分子受体亲和力的异同,Averaged from cloned human receptor data from the Psychoactive Drug Screening Program database(http:/pdsp.med.unc.edu/pdsp.php),and references therein,JA Gray and BL Roth Molecular Psychiatry(2007)12,904922,帕利哌酮阻断2受体 促进NE和5-HT的释放,Averaged from cloned human receptor data from the Psychoactive Drug Screening Program database(http:/pdsp.med.unc.edu/pdsp.php),and references therein,Stahl SM,Stahls Essential Psychopharmacology 3rd Ed.2008 Page 560,帕利哌酮缓释片显著改善睡眠结构,Luthringer et al.Int Clin Psychopharmacol.2007 Sep;22(5):299-308.,10,Drememcov E,Mansari ME,Blier P(2007)Psychopharmacology 194:63-72,空白对照 X 14 天微泵输注水,利培酮 X 14天皮下注射,帕利哌酮 X 14 天皮下注射,峰电位/10 秒,6.5 mm,6.6 mm,6.8 mm,7 mm,6.3 mm,6.4 mm,6.45mm,6.8 mm,6.85 mm,6.95 mm,7 mm,背侧缝隙核5HT神经元放电的差异,峰电位/10 秒,峰电位/10 秒,11,对中脑蓝斑核NE神经元放电的影响,Drememcov E,Mansari ME,Blier P(2007)Psychopharmacology 194:63-72,*p0.001,*p0.01，对照组#p0.001,#p0.01，与单独使用艾司西酞普兰相比IV:静脉注射;SI:皮下注射,X 2 天 IV,X 14 天 SI,帕利哌酮具有NE激活效应，而持续注射利培酮并无NE激活现象,5-HT和NE神经元放电与抑郁和阴性症状关系密切,空白对照,艾司西酞普兰 10 mg/kg.day,NE 神经元放电率(峰电位/sec SEM),帕利哌酮1 mg/kg.day,对照组,14,Seeman P.Expert Opin.Ther.Targets 2006;(10)4:515-531,D2受体快速解离的药物不会引起或仅引起轻微EPS,更有利于阴性、情感、认知功能的改善更少的EPS发生,15,帕利哌酮分子对D2受体的快速解离,P-糖蛋白抑制剂致其底物利培酮蓄积：发生显著EPS,17,1 小时,握杆时间(s),对照组,PSC 833,与对照组(*p0.05)和利培酮组(*p0.05)具显著差别,Pacchioni AM et al.Int J Neuropsychopharmacology,Page 1 of 11.Copyright f CINP 2009 doi:10.1017/S1461145709990782,60分钟,180分钟,300分钟,PSC 833(100 mg/kg p.o.),利培酮(0.01 0.4,or 4 mg/kg s.c.),18,Zhu et al Neuropsychopharmacology(2007)32,757764,1,0.8,0.6,0.4,0.2,0,对照,1,5,10,50,100,多柔比星(阿霉素)的蓄积浓度(nmol/mg),帕利哌酮(M),*,*,1,5,10,50,100,利培酮(M),*,*,*,*,帕利哌酮对P-糖蛋白无抑制作用利培酮对P-糖蛋白具有显著抑制作用,P-糖蛋白抑制作用比较,抗精神病药物是CYP多种同功酶的底物依赖一种或多种酶代谢,21,CYP450同功酶的诱导剂与抑制剂,Odou P et al(2000)Clin Drug Invest 19(4):283-292,23,依赖CYP同功酶代谢药物，药物间相互作用复杂,3A4 抑制剂：甲氰咪胍、氟西汀、氟伏沙明、葡萄柚汁(肠道)、奈法唑酮3A4 诱导剂：巴比妥、卡马西平、莫达非尼、苯妥英钠、贯叶连翘、托吡酯2D6 抑制剂：安非他酮、甲氰咪胍、度洛西汀、氟西汀、帕罗西汀、氟哌丁苯、酚噻嗪、哌迷清、舍曲林、三环类抗抑郁药,Odou P et al(2000)Clin Drug Invest 19(4):283-292,曲线1:单药治疗(虚线99%CI),曲线 2 合并CYP3A4 and CYP2D6 抑制剂,曲线3:合并CYP3A4诱导剂,曲线4:合并CYP3A4诱导剂和CYP3A4与CYP2D6 抑制剂,240,200,160,120,80,40,0,活性部分(g/L),0,0.04,0.08,0.12,0.16,0.20,日常剂量(mg/kg),患者 A,患者 A：疑似慢代谢患者CYP=细胞色素 P450,帕利哌酮分子不依赖CYP酶系代谢,24,25,OROS缓释剂型获取平稳血药浓度,利培酮 IR 2 mg(D1)+4 mg(D2-D6),平均血浆浓度(ng/mL),1 2 3 4 5 6 7,时间（天）,6050403020100,*Simulated by the steady state concentration profile following administration of paliperidone ER(6 mg)once daily for 6 days compared with risperidone IR administered with 2 mg once daily on Day 1 followed by 4 mg once daily on days 2-6Data on file:Johnson&Johnson Pharmaceutical Research&Development,LLC.,血,Paliperidone IR-immediate-release paliperidone;Paliperidone ER-paliperidone extended-release tablets,(64-83%),Karlsson P,et al.Presented at American Society for Clinical Pharmacology and Therapeutics;March 8-11,2006;Baltimore,MD.,脑,Paliperidone ER reduced D2 Occupancy Fluctuation by 1/6 compared to risperidone,缓释剂型血药浓度波动显著小于速释剂型,帕利哌酮 ER的多巴胺受体的占有率峰谷浓度波动仅为利培酮速释片的1/6,1,Stahls essential psychopharmacology 3rd edition,2008,2,Karlsson P,et al.Presented at American Society for Clinical Pharmacology and Therapeutics;March 8-11,2006;Baltimore,MD.,时间（小时）,纹状体D2受体占有率(%),D2受体在两次给药冲击间期必须有充分的占据，以免带来症状波动1帕利哌酮.ER谷浓度波动很小2，症状平稳改善；帕利哌酮.ER峰浓度波动很小2，不良反应更少；,利培酮,2-4,1-2,3-6,4-8,3mg,2mg,1mg,BID,BID,BID,BID,第一天,QD,4mg,天,帕利哌酮 ER,有效剂量,起始剂量即有效剂量,缓慢的剂量滴定,帕利哌酮缓释片不需要滴定,6mg,31,多个大样本试验数据汇总分析 总体AE(5%)对比,利培酮口服 46 mg/d vs 帕利哌酮 ER 612 mg/d,*如果(利培酮-安慰剂(利培酮)帕利哌酮-安慰剂(帕利哌酮)2%.所有不良反应都是指治疗终点时,Schooler N et al.Poster presented at ACNP;December 37,2006;Hollywood,FL,USA,*如果(利培酮-安慰剂(利培酮)帕利哌酮-安慰剂(帕利哌酮)2%.所有不良反应都是指治疗终点时,利培酮口服 24 mg/d vs 帕利哌酮 ER 612 mg/d,Schooler N et al.Poster presented at ACNP;December 37,2006;Hollywood,FL,USA,多个大样本试验数据汇总分析 总体AE(5%)对比,34,帕利哌酮缓释片,利培酮速释片,芮达是新分子和新剂型的创新结合在疗效、安全性和社会功能方面带来更佳获益,
