Non–steady State Analysis of the Pharmacokinetic Interaction between Propofol and Remifentanil

Background The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil. Methods Twenty healthy volunteers aged 20–43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion via a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0–4 &mgr;g/ml and 0–4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography–mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term. Results The concentration–time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol. Conclusions Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma–effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.