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CCR 20th Anniversary Commentary: Determining a Pharmacokinetic/ Pharmacodynamic Relationship for Sunitinib-A Look Back

机译:CCR 20周年评论:确定Sunitinib-A回头的药代动力学/药物动力学关系

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The article by Mendel and colleagues, published in the January 1, 2003, issue of Clinical Cancer Research, described their novel preclinical approach to developing a thorough understanding of the exposure-activity relationship for sunitinib, a multitargeted receptor tyrosine kinase inhibitor being developed for oncology therapy. This work successfully set exposure guidelines to identify a biologically active dose in early clinical trials. Sunitinib (SU11248), which was discovered at SUGEN/Phar-mada in 2000 and became part of the Pfizer portfolio following completion of the acquisition of Pharmacia by Pfizer in 2003, is a small-molecule, receptor tyrosine kinase (RTK) inhibitor that was designed to selectively target the class III/V RTKs, including the vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), FLT3, and KIT. By virtue of targeting these RTKs, it was expected that sunitinib would exhibit a dual mechanism to benefit patients with cancer, first, direct antitumor activity against tumors that express and rely on one or more targets for tumor cell proliferation and/or survival [e.g., mutated KIT in gastrointestinal stromal tumors (GIST) and mutated FLT3 in acute myelogenous leukemia (AML)], and second, to provide potent antiangiogenic activity by targeting VEGFR2 and PDGFRfS. Sunitinib, under the commercial name Sutent, initially received marketing approval from the FDA in 2006 for the treatment of advanced renal cell carcinoma and GIST after disease progression on, or intolerance to, imatinib mesylate. It has subsequently been approved to treat progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease. The studies reported by Mendel and colleagues (1) incorporate a novel approach focused on understanding the pharmacokinetic/ pharmacodynamic (PK/PD) relationship for the efficacy of sunitinib in preclinical models that could be used to help guide early clinical development, including selection of a biologically active clinical dose rather than the more traditional maximum tolerated dose.
机译:孟德尔及其同事的文章在2003年1月1日发表的临床癌症研究,描述了他们对苏替尼的曝光活动关系的彻底理解,描述了潮尼的曝光活动关系的新型临床前进方法,这是一种用于肿瘤的多元受体酪氨酸激酶抑制剂治疗。这项工作成功地设定了暴露指南,以鉴定早期临床试验中的生物活性剂量。在2000年在Sugen / Phar-Mada发现的Sunitinib(SU11248),并成为2003年辉瑞预辉瑞制药机获取后PFizer组合的一部分,是一种小分子,受体酪氨酸激酶(RTK)抑制剂设计用于选择性地靶向III类/ V RTAK,包括血管内皮生长因子受体(VEGFR),血小板衍生的生长因子受体(PDGFR),FLT3和试剂盒。凭借这些RTK的典范,预计Sunitinib将表现出一种双重机制,使患有癌症的患者,首先,针对表达并依赖于肿瘤细胞增殖和/或存活的一种或多种靶标的肿瘤的直接抗肿瘤活性[例如,胃肠道基质肿瘤(GIST)中的突变试剂盒和急性髓性白血病(AML)的突变FLT3],第二,通过靶向VEGFR2和PDGFRF来提供有效的抗血管活性。在商业名称SUTENT下,孙尼尼将于2006年从FDA获得营销批准,用于治疗疾病进展或不耐受,伊马替尼甲磺酸盐的疾病进展后晚期肾细胞癌和GIST。随后已被批准用于治疗患者的逐步,良好的胰腺神经内分泌肿瘤,患者患者,局部晚期或转移性疾病。孟德尔及其同事报告的研究(1)纳入了一种专注于理解Sunitinib在临床前模型中的药代动力学/药效学(PK / PD)关系的新方法,这些方法可用于帮助指导早期临床发展,包括选择A.生物活性临床剂量而不是更传统的最大耐受剂量。

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