Wednesday, August 17, 2022
8/17/2022
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.
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