Development of Pharmacokinetic Models to Characterize the Disposition of New Ant

一个成功的药物开发计划需要对被评估药物的临床药理学有全面的了解。临床药理学部门(CPS)主要关注药代动力学和药效学概念在新型抗癌药物开发中的应用。CPS直接负责在NCI内进行的许多I期和II期临床试验的药代动力学/药效学分析。此外，CPS还为在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。在这一节中，我们使用分隔和非分隔的方法来定义代理的处置。此外，我们经常需要通过体外技术来表征新制剂的血浆蛋白结合特性和新陈代谢。我们的几个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最有经验的药物包括：苏拉明、苯乙酸苯酯、苯丁酸酯、TNP-470、PMEA、AZT、PSC 833、CAI、DAB486IL2、Ig G-RFB4-SMPT-DGA CD22、Ig G-HD37-SMPT-DGA CD19、奥马铂、UCN-01、黄匹利多、沙利度胺、9AC、腹腔注射顺铂、卡铂、多西紫杉醇、多西紫杉醇、帕罗沙星和紫杉醇。目前，我们正在研究PSC 833在长春花碱和紫杉醇作用下多日给药的药代动力学。这是通过临床药代动力学数据以及体外代谢研究来描述PSC 833和这些药物之间的任何相互作用的一种尝试。最近，我们完成了基质金属蛋白酶抑制剂Col-3的I期试验。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.