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Abstract

A continuous fentanyl infusion was administered to eight adult, male beagle dogs for a duration of ˜400 min at a rate of 30 μg/kg/h. The extent of respiratory depression was quantified by continuous, noninvasive, transcutaneous pCO2 recordings. Upon reaching a pseudo-steady-state of respiratory depression at ˜120 min of fentanyl infusion, the animals then received, in a 2×2 crossover fashion separated by ˜3 weeks, 30-minute equiefficacious infusions of nalmefene (12 μg/kg/h) or naloxone (48 μg/kg/h). Multiple venous blood samples were taken throughout the dosing regimen, and the resulting fentanyl, nalmefene, or naloxone plasma concentrations were determined. The concentration—time data were analyzed by noncompartmental methods and subsequently linked to the pharmacodynamic effect data by a competitive antagonism link model. Separately, the biophase concentrations were linked to the plasma concentration—time profiles through a single-exponential conduction function. The various pharmacokinetic/pharmacodynamic parameters resulting from this semiparametric analysis were analyzed by ANOVA, using a statistical model that considers carryover effects. The results of these analyses indicate that several pharmacokinetic/pharmacodynamic parameters of the two antagonists were comparable. However, nalmefene had a significantly more protracted terminal disposition and a significantly greater persistency in the biophase evaluated over the experimental time frame from 0 to 450 min.