Adaptive feedback control for the high-precision management of in-tissue drug concentrations

The recent availability of a technology providing real-time, seconds-resolved in vivo drug concentration measurements has opened the door to performing fully autonomous, closed-loop feedback control over drug dosing. The controllers employed in prior demonstrations of such dosing, however, were designed and optimized using population-based pharmacokinetic models. In the face of individual pharmacokinetic variation (between subjects or even within a single subject over time as their physiology varies), these controllers must be set rather conservatively so as to avoid potentially dangerous overshooting. This, however, slows the speed with which they achieve the desired set point and opening the possibility of their nevertheless still overshooting if the response of a subject differs too much from that of the "average" subject. To address these issues, here we have developed an adaptive feedback-control system that, rather than employing population-pharmacokinetic information, instead uses real-time drug concentration measurements to individualize drug delivery to the specific subject, "on the fly." To achieve this, the system estimates the pharmacokinetics of the individual subject during the initial stages of the infusion, and then continuously updates this subject-specific pharmacokinetic model to maintain effective controller performance even in the face of physiological variations brought on, for example, by changing health status. Using this approach, we then demonstrate a feedback controller that rapidly (20-30 min) achieves and accurately (5%-12% root-mean-squared deviations, though this also includes sensor noise) maintains pre-defined concentrations of the anesthetic procaine in the ventricles of live rats, an application that, due to the delays associated with intracranial drug transport, represents a particular challenge for feedback-controlled intravenous drug delivery. Given the precision and accuracy it achieves in our rat animal model, we believe that the use of adaptive feedback control will ultimately enable safer, more precise drug dosing in humans.