Development of Pharmacokinetic Models to Characterize the Disposition of New Ant

一个成功的药物开发项目需要对被评估药物的临床药理学有全面的了解。临床药理学部分（CPS）的主要兴趣是在新型抗癌药物的开发中使用药代动力学和药效学概念。CPS直接负责NCI进行的大量I期和II期临床试验的药代动力学/药效学分析。此外，CPS为校外社区其他地方进行的许多研究提供了直接的药代动力学支持。在本节中，我们利用隔区和非隔区方法来定义代理的处置。此外，我们经常需要通过体外技术表征新药物的血浆蛋白结合特性和代谢。我们的一些临床试验使用了带有反馈机制的自适应控制来针对特定的血浆浓度（例如苏拉明，CAI）。CPS经验最丰富的药物包括：苏拉明、苯乙酸、苯丁酸、TNP-470、PMEA、AZT、PSC 833、CAI、DAB486IL2、IgG-RFB4-SMPT-dgA CD22、IgG-HD37-SMPT-dgA CD19、奥马铂、UCN-01、黄哌啶醇、沙利度胺、9AC、腹腔顺铂、腹腔卡铂、沉积肽、多西紫杉醇、紫杉醇。目前，我们正在研究多天给药PSC 833与长春花碱和紫杉醇联合使用时的药代动力学。这是在临床药代动力学数据和体外代谢研究中，试图表征PSC 833与这些药物中的任何一种之间的任何相互作用。最近，我们已经完成了COL-3（一种基质金属蛋白酶抑制剂）的一期临床试验。我们正在启动CC5013和2ME的I期试验，这两种药物都是血管生成抑制剂。

A successful drug development program requires a complete understanding of the clinical pharmacology of the agents being evaluated. The Clinical Pharmacology Section (CPS) has as its primary interest the use of pharmacokinetic and pharmacodynamic concepts in the development of novel anticancer agents. The CPS is directly responsible for the pharmacokinetic/pharmacodynamic analysis of numerous Phase I and II clinical trials conducted within the NCI. In addition, the CPS provides direct pharmacokinetic support for many studies performed elsewhere in the extramural community. Within the section, we utilize compartmental and noncompartmental approaches to define the disposition of agents. Also, we are often required to characterize the plasma protein binding properties and metabolism of new agents through in vitro techniques. Several of our clinical trials have used adaptive control with a feedback mechanism to target particular plasma concentrations (e.g., suramin, CAI). The drugs with which the CPS has had its greatest experience include: suramin, phenylacetate, phenylbutyrate, TNP-470, PMEA, AZT, PSC 833, CAI, DAB486IL2, IgG-RFB4-SMPT-dgA CD22, IgG-HD37-SMPT-dgA CD19, ormaplatin, UCN-01, flavopiridol, thalidomide, 9AC, intraperitoneal cisplatin, intraperitoneal carboplatin, depsipeptide, docetaxel, perifosine, and paclitaxel. Currently, we are characterizing the pharmacokinetics of multiple day dosing of PSC 833 when administered with vinblastine and paclitaxel. This is an attempt to characterize any interactions between PSC 833 and either of these agents both in the clinical pharmacokinetic data, as well as through in vitro metabolism studies. Recently, we have completed a Phase I trial of COL-3, a matrix metalloproteinase inhibitor. We are initiating a Phase I trial of CC5013 and 2ME, both angiogenesis inhibitors.