A control system for closed loop control of administration of at least one drug to a patient, the control system comprising: a drug administration actuator connectable to a source of the at least one drug and to a patient for administration of the at least one drug to the patient at a controllable drug dosage rate; one or more monitors for sensing one or more monitored physiological characteristics of the patient and determining therefrom a monitor measurement indicative of an effect of the at least one drug on the patient; and a processor configured, for each of a series of time steps, to determine a control signal (u(t)) and supply the control signal to the drug administration actuator to thereby cause the drug administration actuator to administer the at least one drug to the patient at a drug dosage rate which causes the monitor measurement to track a reference level; wherein the processor is configured to implement a closed loop model-predictive control scheme which comprises, for each of the series of time steps, minimizing a cost function (performance index) subject to one or more constraints to thereby determine the control signal, the cost function based at least in part on the reference level and the monitor measurement; characterized in that the processor is configured to use the control signal as an input to an auxiliary model and to use the auxiliary model and the control signal to estimate at least one concentration level (C, C p ) of the at least one drug in the patient; and wherein the one or more constraints comprise at least one constraint on the estimate of the at least one concentration level of the at least one drug. a drug administration actuator connectable to a source of the at least one drug and to a patient for administration of the at least one drug to the patient at a controllable drug dosage rate; one or more monitors for sensing one or more monitored physiological characteristics of the patient and determining therefrom a monitor measurement indicative of an effect of the at least one drug on the patient; and a processor configured, for each of a series of time steps, to determine a control signal (u(t)) and supply the control signal to the drug administration actuator to thereby cause the drug administration actuator to administer the at least one drug to the patient at a drug dosage rate which causes the monitor measurement to track a reference level; wherein the processor is configured to implement a closed loop model-predictive control scheme which comprises, for each of the series of time steps, minimizing a cost function (performance index) subject to one or more constraints to thereby determine the control signal, the cost function based at least in part on the reference level and the monitor measurement; characterized in that the processor is configured to use the control signal as an input to an auxiliary model and to use the auxiliary model and the control signal to estimate at least one concentration level (C, C p ) of the at least one drug in the patient; and wherein the one or more constraints comprise at least one constraint on the estimate of the at least one concentration level of the at least one drug. <EOS>