Pharmacokinetic-based minibolus delivery as an alternative to continuous infusion for drugs that exhibit a biophase lag.

The presence of a biophase compartment in a pharmacokinetic model indicates that the response to an administered dose of drug is damped such that the time to peak effect occurs after the peak concentration in the bloodstream. This phenomenon, which is common to most intravenous anesthetic agents, can be exploited by a drug delivery method that administers minibolus doses of drug rather than a continuous infusion. Through analysis of the frequency response behavior of the biophase compartment, a bolus magnitude and dose frequency or interval (1/frequency) can be chosen such that the oscillation in drug effect is minimized even though the plasma concentration may be changing significantly with each supplemental dose. A pharmacokinetic and pharmacodynamic based method for calculating the bolus dose size and dosing interval is presented. The trade-off between dose interval and change in drug effect is exemplified through computer simulation of this strategy applied to delivery of the neuromuscular blocking agent pancuronium. The method provides a repetitive perturbation to the pharmacokinetic and pharmacodynamic system that can aid in model parameter identification during closed loop applications.