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.