Closed-loop stability of pharmacokinetic-pharmacodynamic models

In automatic feedback control of intravenous drug infusions, convergence to the setpoint is an important objective. This paper examines the stability of pharmacokinetic-pharmacodynamic models of patient response regulated with proportional integral feedback. The model consists of three components: linear compartmental pharmacokinetics, a first-order lag, and sigmoidal static pharmacodynamics. The permitted pharmacokinetic models obey the principle of detailed balance and admit drug administration into and sampling from the same compartment. Convergence to the setpoint occurs if the reset time of the controller is greater than the maximum possible time constant of the first-order lag. The convergence analysis uses standard Popov stability theory and takes advantage of the little known fact that many pharmacokinetic models possess poles and zeros that alternate on the negative real axis.