Anesthesiology 2002; 97:1350 – 62 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Non–steady State Analysis of the Pharmacokinetic Interaction between Propofol and Remifentanil Thomas Bouillon, M.D.,* Joergen Bruhn, M.D.,* Lucian Radu-Radulescu, M.D.,* Edward Bertaccini, M.D.,† Sang Park, Ph.D.,‡ Steven Shafer, M.D.§ 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 g/ml and 0 – 4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood sam- ples 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 explor- atory analysis for hypothesis generation, pharmacokinetic in- teraction 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-compart- ment model, respectively. In the concentration range exam- ined, 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 concen- tration-dependent in the examined concentration range of propofol. Conclusions: Coadministration of propofol decreases the bo- lus dose of remifentanil needed to achieve a certain plasma– effect compartment concentration but does not alter the respec- tive maintenance infusion rates and recovery times to a clinically significant degree. THE pharmacokinetics of propofol 1–14 and remifen- tanil 15–22,23 have been extensively investigated. Al- though propofol and remifentanil are frequently coad- ministered in clinical practice, very little is known about their pharmacokinetic and pharmacodynamic interac- tion. The purpose of this investigation was to quantify the extent of pharmacokinetic interaction between propofol and remifentanil in the clinically relevant con- centration range. Methods Subjects The study was approved by the Stanford University Institutional Review Board. Written informed consent was obtained from each subject. Ten male and 10 female healthy volunteers (median age, 33.5 yr [range, 20 – 43 yr]; median weight, 69.3 kg [range, 50 –120 kg]) were studied. All volunteers underwent a physical examina- tion, laboratory tests (complete blood cell count, blood chemistries [SMA 20]), and an electrocardiogram. Study Design This was a randomized prospective open-label study. After arrival at the operating room, an electrocardio- graph, a pulse oximeter, and a noninvasive blood pres- sure monitor were attached to the volunteer. Thereafter, two intravenous cannulae for drug and fluid administra- tion were placed in a forearm vein on each arm. A 20-gauge plastic cannula was inserted into the radial artery of the nondominant hand for blood sampling. The volunteers received 30 ml magnesium citrate and were supplied with a tight-fitting facemask for the determina- tion of dead space and carbon dioxide responsiveness necessitated by pharmacodynamic aspects of the study and breathed 100% oxygen throughout the drug admin- istration period. Ventilation and end-tidal carbon dioxide pressure were measured and recorded continuously with an anesthesia monitor (Datex, AS3; Helsinki, Finland). Drugs were administered via target controlled infusion with a Harvard infusion pump (Harvard Clinical Technol- ogy, Inc., South Natick, MA) driven by STANPUMP run- ning on a commercially available laptop computer. The propofol pharmacokinetic parameters were the non– weight-adjusted set reported by Schnider et al. 11 The remifentanil pharmacokinetics were the weight-adjusted set reported by Minto et al. 23 The administration schedule was optimized for a single drug pharmacodynamic study (respiratory depression) followed by a pharmacodynamic interaction study (central nervous system depression). Throughout the study, the attending anesthesiologist could administer additional drugs as deemed necessary. The main * Research Fellow, † Assistant Professor, § Professor, Department of Anesthe- siology, Stanford Medical School. ‡ Senior Research Scientist, Department of Anesthesiology, University of Seattle, Seattle, Washington. Received from the Department of Anesthesiology, Stanford Medical School, Stanford, California. Submitted for publication April 17, 2001. Accepted for publication May 30, 2002. Supported by the Merit Review Program of the Department of Veterans Affairs, Washington, DC, and grant No. Bo-1497 from the Deutsche Forschungsgemeinschaft, Bonn, Germany (to Dr. Bouillon). Address reprint requests to Dr. Bouillon: Department of Anesthesiology, Lei- den University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands. Address electronic mail to: tbouillon1@hotmail.com. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org.  Available at no charge from Steven Shafer, M.D., Professor of Anesthesia, Department of Anesthesia, Stanford Medical School, Stanford, California, at http://anesthesia.stanford.edu/pkpd/. 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