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Pharmacokinetic strategies to optimize IP chemotherapy

优化IP化疗的药代动力学策略

基本信息

批准号：
7646274
负责人：
Joseph P Balthasar
金额：
$ 25.6万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-13 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7646274
关键词：
Adjuvant Angiogenesis Inhibitors Animal Model Animals Antibodies Antineoplastic Agents Binding Blood Blood flow Bone Marrow Cells Cessation of life Clinical Research Data Development Diagnosis Disease Dose Drug Delivery Systems Drug Efflux Drug Exposure Drug Kinetics Drug toxicity Emulsions Excision Exposure to Fat emulsion Greater sac of peritoneum Human Immunoglobulin G In Vitro Intra-abdominal Investigation Laboratories Lead Lipids Lipoproteins Literature Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Maximum Tolerated Dose Methods Micrometastasis Modeling Mus Operative Surgical Procedures Patients Penetration Peritoneal Peritoneum Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phase Plasma Reaction Time Relative (related person)Research Personnel Residual Tumors Safety Series Testing Therapeutic Tissues Toxic effect Treatment Efficacy United States Vinorelbine Work Xenograft Model base bevacizumab chemotherapy clinically relevant cytotoxicity improved in vivo interest intraperitoneal neoplastic cell peritoneal cancer theories treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of gynecologic cancer death in the United States, and there is substantial need for the development of improved strategies to treat this disease. The long-term objectives of this proposal are to develop and test approaches for increasing the safety and efficacy of the chemotherapy of peritoneal tumors, such as those found in patients with advanced ovarian cancer. Based on pharmacokinetic theory, we have proposed "inverse targeting" strategies that utilize adjuvant agents (e.g., anti-drug antibodies, lipid emulsions) to impart regio-selective alterations in drug disposition, thereby enhancing the therapeutic selectivity of intraperitoneal (i.p.) chemotherapy. Additionally, based on pharmacokinetic theory regarding the limiting effects of tumor blood flow on the depth of drug penetration within peritoneal tumors, we have proposed that anti-angiogenic agents may be used to produce tumor-specific increases in drug exposure following i.p. chemotherapy. Work proposed in Aim #1 will investigate the determinants of anti-drug antibody effects on the systemic exposure of antineoplastics following i.p. administration, and clinically relevant murine xenograft models of human ovarian cancer will be employed to test the hypotheses that anti-drug antibodies will increase the pharmacokinetic selectivity and therapeutic selectivity of i.p. chemotherapy. Aim #2 will examine the effects of lipid emulsions on the disposition, toxicity, and anti-tumor effects of vinorelbine (a model lipophilic anti-cancer drug). This work will test hypotheses related to the use of exogenous lipid to modulate drug - lipoprotein interactions, as a means of inducing regio-specific alterations in pharmacokinetics and pharmacodynamics. Aim #3 will employ anti-VEGF antibodies to test the hypothesis that anti-angiogenic therapy will increase drug exposure in peritoneal tumors following i.p. chemotherapy. The proposed work, which builds on exciting preliminary data, will allow further development of improved strategies for the treatment of ovarian cancer.

描述（由申请人提供）：卵巢癌是美国妇科癌症死亡的主要原因，并且非常需要开发治疗这种疾病的改进策略。该提案的长期目标是开发和测试增加腹膜肿瘤化疗的安全性和有效性的方法，例如在晚期卵巢癌患者中发现的那些。基于药代动力学理论，我们提出了利用佐剂（例如，抗药物抗体、脂质乳剂）以赋予药物分布的区域选择性改变，从而增强腹膜内（i. p.）化疗此外，基于药物动力学理论，肿瘤血流对腹膜肿瘤内药物渗透深度的限制作用，我们提出，抗血管生成剂可用于在腹膜内化疗后产生肿瘤特异性药物暴露增加。目标1中提出的工作将研究腹膜内给药后抗药抗体对抗肿瘤塑料全身暴露量影响的决定因素，并将采用临床相关的人卵巢癌小鼠异种移植模型来检验抗药抗体将增加腹膜内化疗的药代动力学选择性和治疗选择性的假设。目的#2将检查脂肪乳剂对长春瑞滨（一种模型亲脂性抗癌药物）的处置、毒性和抗肿瘤作用的影响。这项工作将检验与使用外源性脂质调节药物-脂蛋白相互作用相关的假设，作为诱导药代动力学和药效学区域特异性改变的一种手段。目的#3将采用抗VEGF抗体来检验抗血管生成治疗将增加腹膜内化疗后腹膜肿瘤中药物暴露的假设。这项基于令人兴奋的初步数据的拟议工作将允许进一步开发卵巢癌治疗的改进策略。