Nanodosing: A path to higher sensitivity and lower toxicity pharmaceuticals

纳米剂量：获得更高灵敏度和更低毒性药物的途径

• 批准号: 7328486
• 负责人: JAMES F KRONAUGE
• 金额: $ 13.08万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7328486
• 关键词: Active Biological Transport; Adrenergic Agents; Adult; Animals; Award; Biodistribution; Cardiac; Cells; Chemicals; Chemistry; Child; Clinical; Clinical Research; Clinical Trials; Commit; Condition; Contracts; Critical Pathways; Cyclic GMP; Cyclotrons; Data; Detection; Development; Diagnostic; Diagnostic Sensitivity; Documentation; Dose; Drug Formulations; Drug Kinetics; Drug Utilization; Drug or chemical Tissue Distribution; End Point; Equipment; Exposure to; Funding; Generic Drugs; Goals; Grant; Guanosine Monophosphate; Half-Life; Heart; Heart Neoplasms; Human; Human Volunteers; I131 isotope; Image; Iodine; Isotopes; Label; Legal patent; Malignant Neoplasms; Measures; Medical center; Metabolic Clearance Rate; Methods; Molecular; Names; Neuroendocrine Tumors; Neurons; Neurosecretory Systems; New-Fill; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Organ; Orphan Drugs; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Polymers; Polystyrenes; Procedures; Process; Prodrugs; Production; Property; Radiation; Radio; Radioactive; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Range; Rattus; Reaction; Relative (related person); Reporting; Research Ethics Committees; Running; S Phase; Safety; Sensitivity and Specificity; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solid; Solutions; Staging; Standards of Weights and Measures; Sterility; Sterilization for infection control; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Equivalency; Time; Tissues; Toxic effect; United States Food and Drug Administration; United States National Institutes of Health; Validation; Vial device; Writing; adrenergic; analytical method; base; day; dosimetry; expiration; healthy volunteer; innovation; insight; metaiodobenzylguanidine; noradrenaline transporter; novel; novel diagnostics; preclinical study; prospective; quality assurance; radiochemical; radiotracer; scale up; success; tumor; tumor xenograft; uptake; volunteer

DESCRIPTION (provided by applicant): Current availability of iobenguane I 123 is limited to single doses labeled at regional radiopharmacies with variable formulations and specific activities. The objective of this Fast track phase 1/2 SBIR is to produce and perform safety testing in humans of a new diagnostic drug product formulation of iobenguane I 123. The justification for requesting Fast Track consideration is to take advantage of the synergy of developing a diagnostic version of the high specific activity iobenguane I 123 using starting materials and facilities established for the development of the therapeutic I-131 agent. The goal of this proposal is to produce and test high specific activity Ultratrace iobenguane I 123 in normal human volunteers. The low specific activity iobenguane I 123 has been shown to be useful for the detection and staging of neuroendocrine tumors in adults and children and imaging neuronal activity in the heart. The innovation in this proposal is through the use of patented solid phase technology to produce a proven diagnostic agent at extremely high specific activity to increase sensitivity and specificity and lower radiation exposure to normal organs without the pharmacologically active cold carrier compound. The FDA considers iobenguane labeled with two different isotopes of iodine [I 131 and I 123] as two distinct drugs requiring distinct regulatory applications. To meet the required quality standards for the chemistry, manufacturing and controls component of an IND application, GMP quality polymer drug precursor will be used to generate the Ultratrace diagnostic iodine- 123 agent. Analytical methods must be validated with the proposed final drug formulation to demonstrate the final drug does not interfere with tests used to define the identity, purity, and strength of the agent. The drug product solution must also be verified to be apyrogenicity and sterility before human testing can be initiated. The formulation of the final drug product will be tested for stability and bioequivalence in norepinephrine-transporter expressing cells and in animals. The required IND application will be written and submitted to the FDA and the Duke Medical Center IRB. MIP will produce clinical trial material and conduct human testing of the radioactive drug substance for safety and superiority compared to conventional iobenguane I 123 in normal healthy volunteers.

说明(由申请人提供)：目前可获得的Iobenguane I 123仅限于地区性放射性药物中标记的单次剂量，具有不同的配方和特定的活性。这项快速通道第1/2期SBIR的目标是生产一种新的诊断药物Iobenguane I 123配方，并在人体上进行安全性测试。申请Fast Track考虑的理由是利用为开发治疗性I-131试剂而建立的原料和设施开发高比活性Iobenguane I 123的诊断版本的协同效应。这项提议的目标是在正常人志愿者中生产和测试高比活性的Ultratrace Iobenguane I 123。低比活度的Iobenguane I 123已被证明对成人和儿童的神经内分泌肿瘤的检测和分期以及心脏神经元活动的成像是有用的。这项建议的创新之处在于，通过使用专利固相技术来生产一种经过验证的具有极高比活性的诊断试剂，以提高敏感性和特异性，并在没有药理活性冷载体化合物的情况下降低对正常器官的辐射暴露。FDA认为，用两种不同的碘同位素[I131和I123]标记的Iobenguane是两种不同的药物，需要不同的监管应用。为了满足IND应用的化学、制造和控制组件所需的质量标准，GMP级高质量聚合物药物前体将用于生产Ultratrace诊断碘-123试剂。分析方法必须与建议的最终药物配方进行验证，以证明最终药物不会干扰用于确定试剂的身份、纯度和强度的测试。在开始人体试验之前，药物产品溶液还必须经过无热性和无菌验证。最终药物产品的配方将在表达去甲肾上腺素转运体的细胞和动物中进行稳定性和生物等效性测试。所需的IND申请将被编写并提交给FDA和杜克医学中心IRB。MIP将生产临床试验材料，并在正常健康志愿者中对这种放射性药物物质进行人体测试，以确定其安全性和优越性，并与常规的Iobenguane I 123进行比较。