Personalized, high-resolution pharmacokinetic measurements to improve drug dosing

个性化、高分辨率的药代动力学测量以改善药物剂量

• 批准号: 8648544
• 负责人: Jacob Somerson
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-21 至 2017-02-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648544
• 关键词: Adverse effects; Animals; Beds; Behavior; Binding; Biosensor; Blood; Blood Vessels; Cell membrane; Charge; Chemistry; Complex; Couples; Detection; Development; Devices; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Ear; Electrodes; Electronics; Equipment; Ethylene Glycols; Event; Exhibits; Exposure to; Feedback; Frequencies; Generations; Goals; Hour; Hydroxyl Radical; In Vitro; Intravenous; Kinetics; Laboratories; Measurement; Measures; Metabolism; Modeling; Monitor; Oligonucleotides; Oryctolagus cuniculus; Outcome; Patients; Performance; Pharmaceutical Preparations; Plasma; Preparation; Process; Regimen; Reporting; Research; Resistance; Resolution; Sampling; Sensitivity and Specificity; Serum; Signal Transduction; Specificity; Surface; Techniques; Technology; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Veins; Whole Blood; aptamer; base; biomaterial compatibility; cancer therapy; clinically relevant; ethylene glycol; improved; in vivo; meetings; monolayer; pharmacokinetic model; programs; public health relevance; response; sensor; small molecule; subcutaneous; technology development

DESCRIPTION (provided by applicant): Drastically variable inter-patient pharmacokinetics remain a significant, unsolved problem in cancer treatment. In response, I propose here the development of technology enabling the real-time, continuous measurement of in vivo drug levels. Such a technology would allow clinicians to move from dosing regimens calculated using imprecise models of pharmacokinetics to regimens based on actual patient-specific, measured pharmacokinetics, thereby "personalizing" drug delivery to improve patient outcomes. Towards this goal, my research program focuses on the development of a new class of reagentless, electrochemical biosensors that supports the continuous, real-time monitoring of chemotherapeutic concentrations in vivo with sub-minute time resolution and clinically relevant sensitivity, specificity and precision. Such a technology would enable personalized, ultra-high-precision dosing possible, enhancing efficacy while decreasing toxicity. Electrochemical aptamer-based sensors can meet this need. This class of sensors couples the selectivity and ease of electrochemical detection with the specificity and versatility of aptamers. These sensors already support quantitative, real-time detection in undiluted blood serum, placing them among the most selective real-time biosensors reported to date. However, continuous exposure to whole blood produces a significant baseline drift of the signaling current. In this proposal, I outline two complementary strategies to reduce the magnitude of this drift and enable correcting signal against this drift to enable this technology for use directly in the blood vessel of an animal. Upon successful in vitro sensing in whole blood, I propose the in vivo testing of an indwelling doxorubicin sensor directly in the marginal ear vein of a rabbit.

描述（由申请人提供）：患者间急剧变化的药代动力学仍然是癌症治疗中一个重要的、未解决的问题。作为回应，我在这里建议开发能够实时、连续测量体内药物水平的技术。这种技术将允许临床医生从使用不精确的药代动力学模型来计算给药方案，转向基于实际的患者特异性、可测量的药代动力学的方案，从而实现“个性化”给药，以改善患者的治疗效果。为了实现这一目标，我的研究项目侧重于开发一种新型的无试剂电化学生物传感器，该传感器支持连续、实时监测体内化疗浓度，具有亚分钟的时间分辨率和临床相关的灵敏度、特异性和精度。这种技术将使个性化、超高精度的给药成为可能，在降低毒性的同时提高疗效。基于电化学适体的传感器可以满足这一需求。这类传感器将电化学检测的选择性和便利性与适体的特异性和通用性结合起来。这些传感器已经支持在未稀释的血清中进行定量实时检测，使其成为迄今为止报道的最具选择性的实时生物传感器之一。然而，持续暴露于全血会产生信号电流的显著基线漂移。在本提案中，我概述了两种互补的策略，以减少这种漂移的大小，并使校正信号对抗这种漂移，使这项技术能够直接用于动物的血管。在全血体外传感成功后，我建议直接在兔耳缘静脉内留置阿霉素传感器进行体内测试。