Simultaneous pharmacometric control optimization for advanced integrated multi-drug target infusions

Accurately controlling drug delivery is crucial for safe anesthesia. Target-controlled infusion (TCI) systems use pharmacokinetic and pharmacodynamic (PK/PD) models to administer intravenous agents to reach target concentrations. However, TCI’s operation is restricted to a single-drug, not accounting for drug interactions. Dose–response interaction (DRI) models quantify such interactions by representing shared effects as a function of agents’ concentrations. We introduce a new administering methodology for multi-drug infusions, interaction target-controlled infusion (iTCI), that combines the PK/PD models of the co-administered drugs and their interactions into a single optimal non-linear dynamic control problem with terminal constraints. The capabilities of the iTCI are shown in different clinical scenarios using different PK/PD models such as Schnider and Eleveld for propofol and Minto for remifentanil. Incorporating DRI and PK/PD models allows novel administration procedures. These show that: (1) iTCI requires lower administered volumes than TCI to simultaneously reach the same target concentrations. (2) It offers optimal interdependent administrations that address not only concentration targets but also effect targets. (3) iTCI comes with additional constraints on the administration, including controlled titrations along iso-effect conditions (isoboles) or (4) directly limiting plasma concentration levels. (5) Unlike TCI, iTCI can include in the control strategy different exerted effects (multiple ke0s) per drug, particularly relevant for opioids. The iTCI is a new versatile open-loop multi-drug infusion paradigm allowing safer and more flexible optimized concurrent administration profiles than traditional TCI solutions. It opens up new possibilities for simultaneous multi-anesthetics controlled administrations where synergies and effects are taken into consideration.