Bio-electrochemical detectors for in vivo continuous monitoring

总结。我们的首要目标是使治疗药物监测变得方便和高度及时。 因为连续的血糖监测仪已经实现了对血糖的监测。这一目标的实现将 改变生物医学研究和临床实践的许多方面。例如，它将使 个性化给药基于患者准确确定的药物代谢，而不是预测不佳的药物代谢， 一种与传染病治疗高度相关的结果，传染病通常使用 危险的狭窄治疗指数，并以改善女性的健康，如药代动力学性别差异 导致女性的不良药物治疗结果增加一倍。最终，这样的技术可能会 实现反馈控制的药物剂量，通过对代谢变化做出实时反应，将改善 具有剂量限制毒性的药物的安全性和有效性。然而，要实现我们的目标，需要 两项重大创新：(1)一种能够原位监测肠液中任意药物分子的技术 (2)极大地改善了对阿司匹林药代动力学的了解 ISF中的药物与血浆中的药代动力学有关。在上一轮拨款计划下，我们 实现了这些必要进展中的第一个。具体地说，我们展示了微创 基于适配子的电化学(EAB)传感器支持秒分辨率的药物实时测量 在我们的活体大鼠动物的血浆(静脉)、脑脊液(脑)和皮下腔(ISF)进行原位观察 模特。在这里，我们提出了解决第二项创新的建议。也就是说，使用静脉和皮下EAB 我们提出的传感器以促进对血浆和ISF药代动力学之间关系的理解 一系列不同的抗菌药物和免疫抑制药物，治疗药物监测是 这是护理标准的重要组成部分。我们相信，由此产生的数量级的改善 测量这些关系是我们实现高精度渲染的长期目标的关键一步 治疗药物监测方便、经济实惠。

Summary. Our overarching goal is to render therapeutic drug monitoring as convenient and highly time resolved as the continuous glucose monitor has rendered the monitoring of blood sugar. The realization of this goal would transform many aspects of both biomedical research and clinical practice. It would, for example, enable personalized dosing based on a patient’s accurately determined, rather than poorly predicted, drug metabolism, an outcome of high relevance to the treatment of infectious diseases, which commonly employs drugs of dangerously narrow therapeutic index, and to improving women’s health, as pharmacokinetic sex differences lead to a doubling of adverse pharmacotherapeutic outcomes in females. Ultimately such a technology could enable feedback-controlled drug dosing, which, by responding in real time to metabolic variations, would improve the safety and efficacy of drugs that suffer from dose-limiting toxicity. To achieve our goal, however, requires two significant innovations: (1) a technology able to monitor arbitrary drug molecules in situ in the intestinal fluid (ISF) of the subcutaneous space and (2) vastly improved knowledge regarding how the pharmacokinetics of drugs in the ISF relate to the pharmacokinetics seen in plasma. Under the prior round of grant funding, we achieved the first of these necessary advances. Specifically, we demonstrated that minimally-invasive Electrochemical, Aptamer-Based (EAB) sensors support the seconds-resolved, real-time measurement of drugs in situ in the plasma (venous), cerebrospinal fluid (brain), and ISF (subcutaneous space) of our live rat animal model. Here we propose to tackle the second innovation. That is, using intravenous and subcutaneous EAB sensors we propose to advance understanding of the relationships between plasma and ISF pharmacokinetics across a diverse set of antimicrobial and immunosuppressant drugs for which therapeutic drug monitoring is an important element of the standard of care. We believe the resulting orders of magnitude improvement in measuring these relationships is a critical step towards our long-range goal of rendering high-precision therapeutic drug monitoring convenient and cost effective.