Pharmacokinetic strategies to optimize IP chemotherapy

优化IP化疗的药代动力学策略

• 批准号: 7286074
• 负责人: Joseph P Balthasar
• 金额: $ 25.53万
• 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/7286074
• 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; Depth; 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; Rate; Reaction Time; Relative (related person); Research Personnel; Residual Tumors; Safety; Series; Statistically Significant; 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; tumor

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，并且非常需要发展治疗这种疾病的策略。该提案的长期目标是开发和测试方法，以提高腹膜肿瘤化学疗法的安全性和功效，例如在晚期卵巢癌患者中发现的方法。基于药代动力学理论，我们提出了利用辅助剂（例如抗药物抗体，脂质乳液）的“逆靶向”策略，以赋予药物处置中的区域性选择性改变，从而增强腹膜内治疗（I.P.）化学治疗的治疗性选择性。此外，基于有关肿瘤血流对腹膜肿瘤中药物渗透深度的限制作用的药代动力学理论，我们提出抗血管生成剂可用于在I.P.后产生药物暴露​​的肿瘤特异性增加。化学疗法。 AIM＃1中提出的工作将研究抗药物抗体对抗肿瘤抗体的全身暴露的决定因素。将采用给药和与临床相关的人类卵巢癌的鼠类异种移植模型来检验抗药物抗体将提高腹腔内药代动力学选择性和治疗性选择性的假设。化学疗法。 AIM＃2将检查脂质乳液对乙烯甲苯甲酸（一种模型亲脂性抗癌药）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脂质调节药物 - 脂蛋白相互作用有关的假设，这是诱导药代动力学和药效学中区域特异性改变的一种手段。 AIM＃3将采用抗VEGF抗体来检验以下假设：抗血管生成疗法将增加腹腔炎后腹膜肿瘤的药物暴露。化学疗法。拟议的工作以令人兴奋的初步数据为基础，将进一步发展改进卵巢癌治疗的策略。