Pharmacokinetic strategies to optimize IP chemotherapy

优化IP化疗的药代动力学策略

• 批准号: 7144306
• 负责人: Joseph P Balthasar
• 金额: $ 27.72万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-13 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144306
• 关键词: antibody; chemotherapy; lipids; neoplasm /cancer; ovary neoplasms; pharmacokinetics

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，并且非常需要开发改进的策略来治疗这种疾病。该提案的长期目标是开发和测试提高腹膜肿瘤化疗安全性和有效性的方法，例如晚期卵巢癌患者的化疗。基于药代动力学理论，我们提出了“反向靶向”策略，利用佐剂（例如抗药抗体、脂质乳剂）来赋予药物处置的区域选择性改变，从而增强腹膜内（i.p.）化疗的治疗选择性。此外，基于关于肿瘤血流对腹膜肿瘤内药物渗透深度的限制影响的药代动力学理论，我们提出抗血管生成剂可用于在腹膜内注射后产生肿瘤特异性药物暴露增加。化疗。目标#1中提出的工作将研究抗药物抗体对腹腔注射后抗肿瘤药物全身暴露影响的决定因素。将采用人类卵巢癌的临床相关小鼠异种移植模型来测试抗药物抗体将增加腹膜内注射的药代动力学选择性和治疗选择性的假设。化疗。目标#2 将研究脂肪乳剂对长春瑞滨（一种亲脂性抗癌药物模型）的处置、毒性和抗肿瘤作用的影响。这项工作将测试与使用外源脂质调节药物-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手段。目标 #3 将采用抗 VEGF 抗体来检验以下假设：抗血管生成治疗会增加腹膜肿瘤中腹膜肿瘤的药物暴露。化疗。拟议的工作以令人兴奋的初步数据为基础，将有助于进一步开发改进的卵巢癌治疗策略。