Abstract 1666: Regorafenib (BAY 73-4506): preclinical pharmacology and clinical identification and quantification of its major metabolites
Abstract 1666: Regorafenib (BAY 73-4506): preclinical pharmacology and clinical identification and quantification of its major metabolites
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摘要 1666：瑞戈非尼 (BAY 73-4506)：临床前药理学及其主要代谢物的临床鉴定和定量
DOI：
10.1158/1538-7445.am10-1666
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发表时间：
2010
期刊：
影响因子：
11.2
通讯作者：
M. Radtke
中科院分区：
文献类型：
--
作者：
D. Zopf;Roland Dr. Heinig;K. Thierauch;C. Hirth‐Dietrich;F. Hafner;O. Christensen;Tiffany Lin;S. Wilhelm;M. Radtke
瑞戈非尼是一种新型的血管生成、基质和致癌激酶的二苯基脲类口服多激酶抑制剂，具有强效的临床前抗肿瘤活性和持久的抗血管生成活性（通过动态对比增强磁共振成像测量）。最近在一项II期研究中，瑞格非尼治疗转移性肾细胞癌患者的部分缓解率（PR）为31%，稳定率为50%。在一项I期研究中，27例可评价的晚期难治性结直肠癌患者（中位4种既往治疗方案）显示了有前景的临床活性，总体疾病控制率为74%（PR +疾病稳定）。在体外用肝微粒体和肝细胞研究了瑞格非尼的生物转化，并在几个种属的血浆中进行了体内研究。在人体中，N-氧化物（M-2）和脱甲基N-氧化物（M-5）表现出显著性，因为在一项给药3周/停药1周的I期研究中，这两种代谢物在稳态时的全身暴露量（曲线下面积[AUC]，mg*h/L）与患者接受160 mg剂量的瑞戈非尼（母体化合物）相似。M-2和M-5的表征均显示出强效的药理活性。在生化激酶试验中，M-2和M-5显示出与瑞戈非尼相似但不同的抑制特征。在细胞试验中，M-2和M-5抑制关键靶点，如血管内皮生长因子（VEGF）受体2、TIE-2、突变型和野生型c-KIT和B-RAF，M-2的IC 50值与瑞戈非尼非常相似，M-5的IC 50值略高。瑞戈非尼以及1 mg/kg iv给药的M-2和M-5在大鼠VEGF抑制药效学模型中显示出显著活性。在临床前鼠HT-29结直肠癌和MDA-MB-231乳腺癌异种移植物中，经口给药的两种代谢物均表现出强效剂量依赖性肿瘤生长抑制（TGI），与10 mg/kg溶剂对照相比，分别达到62/58%和54/50%的显著TGI。在这些模型中，瑞格非尼在10 mg/kg剂量下显示66-77%的TGI。小鼠经口给予瑞戈非尼后，N-氧化物（M-2）血浆水平占瑞戈非尼AUC的20%;相反，给予M-2后，瑞戈非尼暴露量达到M-2暴露量的20%，表明氧化为N-氧化物和还原为体内代谢途径。总之，这些数据表明，代谢物M-2和M-5在人体中表现出与其母体化合物瑞戈非尼相似的暴露量，具有抗肿瘤活性，因此最可能有助于瑞戈非尼的临床抗肿瘤活性。引用格式：{Authors}。【摘要】【摘要】In：Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21;华盛顿，DC. Philadelphia（PA）：AACR; Cancer Res 2010;70（8 Suppl）：Abstract nr 1666.
Regorafenib is a novel diphenylurea oral multikinase inhibitor of angiogenic, stromal, and oncogenic kinases with potent preclinical antitumor activity and long-lasting antiangiogenic activity (as measured by dynamic contrast-enhanced magnetic resonance imaging). Regorafenib treatment has recently shown to result in a 31% partial response (PR) rate and 50% stabilization rate in patients with metastatic renal cell carcinoma in a Phase II study. Promising clinical activity was shown in a Phase I study in 27 evaluable patients with advanced refractory colorectal cancer (median 4 prior regimens) with a 74% overall disease control rate (PR + stable disease). The biotransformation of regorafenib was investigated in vitro with liver microsomes and hepatocytes, and in vivo in the plasma of several species. In man, the N-oxide (M-2) and the demethylated N-oxide (M-5) appear significant as both metabolites show systemic exposure (area under the curve [AUC], mg*h/L) at steady state similar to regorafenib (the parent compound) in patients at a dose of 160 mg in a 3 weeks on/1 week off Phase I study. Characterization of both M-2 and M-5 demonstrated potent pharmacologic activities. In biochemical kinase assays, M-2 and M-5 showed an inhibition profile similar to but distinct from regorafenib. In cellular assays, M-2 and M-5 inhibited key targets such as vascular endothelial growth factor (VEGF) receptor 2, TIE-2, and mutant and wild-type c-KIT and B-RAF, with IC50 values very similar to regorafenib for M-2 and somewhat higher for M-5. Regorafenib and both M-2 and M-5 dosed iv at 1 mg/kg showed significant activity in a rat VEGF hypotensive pharmacodynamic model. Both metabolites dosed orally exhibited potent dose-dependent tumor growth inhibition (TGI) in preclinical murine HT-29 colorectal and MDA-MB-231 breast cancer xenografts, achieving significant TGI of 62/58% and 54/50%, respectively, compared with vehicle controls at 10 mg/kg. Regorafenib revealed 66-77% TGI at 10 mg/kg in these models. On oral administration of regorafenib to mice, the N-oxide (M-2) plasma level accounted for ∼20% of the AUC of regorafenib; conversely, on administration of M-2, regorafenib exposure reached ∼20% of M-2 exposure, indicating that oxidation to and reduction of the N-oxide are metabolic pathways in vivo. In summary, these data demonstrate that the metabolites M-2 and M-5, exhibiting similar exposure as regorafenib, their parent compound, in man, are pharmacologically active and therefore most likely contribute to the clinical antitumor activity of regorafenib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1666.