医学交流课件：New Products Development Introduction overview (2).pptxVIP

New Products Development Introduction overview Daxas related clinical study introduction --- ChenxiaojunRoflumilast2010年欧洲获批，Daxas2011年美国获批，DALIRESP?GOLD updated 2016作用机制Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells. Roflumilast is the only oral selective phosphodiesterase 4 (PDE4) inhibitor indicated for use in the treatment of COPD. 磷酸二酯酶( PDEs ) :能将细胞内cAMP水解为无活性的单核苷酸。PDE4是cAMP代谢的主要代谢酶。抑制PDE4可引起细胞内cAMP的的聚集。cAMP:可导致支气管平滑肌松弛和抑制肺部炎症反应。药效学In COPD patients, 4 week treatment with DALIRESP 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, DALIRESP 500 mcg once daily reduced the number of total cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown. DALIRESP lable药代动力学吸收：单剂量口服生物利用度80%，空腹给药后平均1小时（0.5~2）达到血浆峰浓度分布： Roflumilast及及其N-oxide血浆蛋白结合率分别是99%和97%，分布容积2.9L/kg，很少穿透血脑屏障代谢： Roflumilast N-oxide是血浆中最主要的代谢产品，尿液中无法检测到Roflumilast，仅能测到少量的N-Oxide清除：Roflumilast及及其N-oxide血浆有效半衰期17~30h，故给药1天1次DALIRESP lableRoflumilast 治疗COPD研究列表Author（Year）PhasePatientsPopulationInterventionControlDurationOutcomeRabe, 2005ⅢModerate to severe COPD1411(576/555/280)roflumilast 250 ugroflumilast 500 ugplacebo24w①②③④⑤⑥⑧⑨Calverley, 2009ⅢSevere to very severe COPD3091(1537/1554)Roflumilast 500ug qdPlacebo52w①②③⑤⑦⑧⑨Fabbri,2009ⅢCOPD with postbronchodilat