Methods of Estimating Plasma Pharmacokinetics From Minimally Invasive, High Temporal Resolution Measurements of Interstitial Fluid Drug Concentrations

In therapeutic drug monitoring, plasma drug concentrations are used to guide dosing decisions, significantly improving outcomes for many therapeutic interventions. Due to the cumbersome, laboratory-based approaches used to measure such drug concentrations, however, such monitoring is slow to return actionable information to the clinician and is performed far less frequently than would be optimal. In response, approaches are being developed by which in vivo drug concentrations can be monitored in real time and at high frequency in the subcutaneous or intradermal interstitial fluid-measurements that are safe, convenient, and minimally invasive. In the furtherance of this approach, here, we explore theoretically the ability to use such high-frequency sub- or intradermal measurements to estimate the corresponding plasma concentration-time courses, as the latter remain the basis of effectively all clinical decision making. Doing so, we find that, given various physiologically and technologically plausible assumptions, it is possible to accurately estimate plasma concentration-time courses from measurements of interstitial fluid taken at two nonredundant sites in the interstitial fluid. This ability to derive clinically important plasma pharmacokinetics using minimally invasive subcutaneous or intradermal sensor placements has the potential to significantly improve the precision and reach of therapeutic drug monitoring and, with that, the safety and efficacy of drug delivery.