Multi-drug interaction target-controlled infusion fromsimultaneous optimization of pharmacometric models

BackgroundAccurately 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, TCIs operation is restricted to a single-drug and a linear PK/PD model, not accounting for drug interactions. Dose-response interaction (DRI) models quantify such interactions by representing shared effects as a function of agents concentrations. For example, the co-administration of an analgesic and a hypnotic with TCI leads to an uncontrolled synergy. MethodsWe 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. ResultsIncorporating DRI and PK/PD models allows novel administration procedures. Simulations of iTCI in different clinical scenarios under propofol and remifentanil co-administrations are presented. These show that: (1) iTCI requires lower administered volumes than TCI to reach simultaneously 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 (5) directly limiting plasma concentration levels. (6) Unlike TCI, iTCI can include different exerted effects (ke0) per drug, particularly relevant for opioids. ConclusionThe iTCI is a versatile multi-drug infusion paradigm where effects and interactions play a relevant role - providing better delivery profiles than current TCI while opening the door for using non-linear PK/PD descriptions in anesthesia.