CLINICAL TRIAL: A PHASE I PHARMACOKINETIC STUDY OF PS-341 IN PATIENTS WITH ADVAN

临床试验：PS-341 在 ADVAN 患者中的 I 期药代动力学研究

• 批准号: 7982071
• 负责人: Stephen I Shibata
• 金额: $ 1.04万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982071
• 关键词: Cancer Patient; Clinical Data; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Cytochrome P450; Drug Exposure; Drug Kinetics; Enzymes; Funding; Grant; Institution; Liver Dysfunction; Mediating; Metabolic Pathway; Metabolism; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Property; Proteasome Inhibition; Proteasome Inhibitor; Protein Binding; Protein Isoforms; Research; Research Personnel; Resources; Source; Toxic effect; Ubiquitin; United States National Institutes of Health; base; drug development; experience; pre-clinical; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major pathway of elimination of PS-341 is metabolism. Metabolism of PS-341 is largely mediated by the cytochrome P450 isoforms 3A4 and 2D6. The major metabolic pathway is deboronation, forming a metabolite with no observed proteasome inhibition properties. The deboronated metabolite subsequently forms a number of hydroxylated metabolites. Protein binding of PS-341 is approximately 84%. Liver dysfunction is not uncommon in cancer patients. Patients with liver dysfunction may experience greater drug exposure and toxicity from many drugs. CYP 450 enzymes metabolize PS-341, therefore patients with liver dysfunction may have different pharmacokinetic and toxicity profiles compared to patients without liver dysfunction. Based on the mechanism of action and the pre-clinical data ubiquitin-proteasome inhibitors may be beneficial in many different tumor types. It is therefore imperative that PS-341 be studied in patients with liver dysfunction for the proper development of this drug that is first in the class of ubiquitin-proteasome inhibitors.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 PS-341 消除的主要途径是代谢。 PS-341 的代谢主要由细胞色素 P450 亚型 3A4 和 2D6 介导。 主要代谢途径是脱硼，形成没有观察到蛋白酶体抑制特性的代谢物。 脱硼代谢物随后形成许多羟基化代谢物。 PS-341 的蛋白结合率约为 84%。 肝功能障碍在癌症患者中并不罕见。肝功能障碍患者可能会经历更多的药物暴露和许多药物的毒性。 CYP 450 酶代谢 PS-341，因此肝功能障碍患者与无肝功能障碍患者相比可能具有不同的药代动力学和毒性特征。根据作用机制和临床前数据，泛素蛋白酶体抑制剂可能对许多不同的肿瘤类型有益。因此，必须在肝功能障碍患者中对 PS-341 进行研究，以便正确开发这种泛素蛋白酶体抑制剂类别中的首个药物。