Titration of the plasma effect site equilibrium rate constant of propofol; a link method of ‘Concentration-Probability-Time’

Abstract

Background: The plasma effect-site equilibrium rate constant (ke0) of propofol has been reported in various pharmacodynamic studies; however, it is not desirable to apply ke0 for the link with pharmacokinetic models that were separately investigated. Thus, we titrated ke0 for the pharmacokinetic model, which is known as the multiple covariates adjusted model of propofol.

Methods: Ninety female patients scheduled for gynecologic surgery were randomly assigned to three groups targeting different plasma concentrations of 5.4, 8.1, and 10.8 μg/ml. Target-controlled infusions (TCI) were provided by a computer-assisted continuous infusion system. Time to loss of responsiveness (LOR) was measured by a blind investigator; effect-site concentrations (Ce) for LOR were then calculated with simulation of TCI using different ke0s. We determined the ke0 minimizing total discrepancy (TD) between the inputted and calculated ke0 from the t1/2ke0s for a given probability of LOR of the Ce, and also obtained the ke0 for the minimal TD between the median Ce, which were compared to the known ke0.

Results: Ke0s from these two methods were 0.3692 and 0.3788/min. Ces for LOR with these ke0s were significantly different from those with Schnider’s ke0.

Conclusions: We proposed a method for titration of the ke0 of propofol. The ke0s of propofol was lower than Schnider’s ke0. An adequate ke0 for the specific pharmacokinetic model and a certain population would be useful for prediction of an accurate Ce, and could be used for calculation of accurate dosing during targeting of the effect site.