Evaluation of a possible drug interaction between remifentanil and esmolol using pharmacokinetic and pharmacodynamic modeling

Abstract

Remifentanil (ULTIVA) is an ultra short-acting opioid which has recently been approved for use during surgical procedures requiring opioid analgesia. After i.v. administration, it is rapidly metabolized by non-specific esterases in the blood and other tissues to less active metabolites. Total body clearance of remifentanil in man is 41.2 mL/min/kg, the Vd is 390 mL/kg and the elimination half-life is 10-48 minutes. In dogs, the clearance is 63 mL/min/kg, Vdss is 222 mL/kg and the elimination half-life is 5.7 minutes. Esmolol is an ultra short-acting beta-blocker administered intravenously during surgical procedures to decrease heart rate and blood pressure in patients at risk of cardiovascular complications. It is also metabolized by non-specific esterases in the blood and other tissues to form an inactive acid metabolite and methanol. It is likely both drugs will be administered together in patients with cardiac disease during surgical procedures. The goal of this study was to evaluate a possible drug interaction between remifentanil and esmolol following concomitant administration. This was accomplished by comparing pharmacokinetic and pharmacodynamic parameters of remifentanil after administration alone and in combination with esmolol. In the first study, remifentanil (treatment I, 25 mug/kg/min) and remifentanil plus esmolol (treatment II, (25 mug/kg/min and 200 mug/kg/min, respectively)) were infused for 20 minutes into male Sprague-Dawley rats in a random parallel design. Arterial blood samples were collected over the course of the study, extracted with methylene chloride, and analyzed (off-site) by a validated GC-MS assay. Additionally, cardiovascular measurements were continuously collected from 15 minutes pre-dose until about 20 minutes after end of infusion. Compartmental modeling was performed to determine the pharmacokinetic parameters. In a follow-up study, remifentanil (treatment I, 15 mug/kg/mL) and remifentanil plus esmolol (treatment II, (15 mug/kg/min and 600 mug/kg/min, respectively)) were infused into male Sprague-Dawley rats in a random two-way cross-over design. Blood samples (using limited sampling strategy) were collected and analyzed as before. EEG data were collected continuously over the course of the study. Bayesian estimation was used to determine the pharmacokinetic parameters. Pharmacodynamic parameters were obtained by modeling EEG spectral edge, using a pharmacokinetic-pharmacodynamic link model. Comparison of the pharmacokinetic and pharmacodynamic parameters between treatments I and II in both studies did not detect any significant (p < 0.05) differences. This indicates that at the doses tested, the co-administration of esmolol did not cause a significant change in the pharmacokinetics or pharmacodynamics of remifentanil no drug-drug interaction.