DURATION OF OPIOID ANTAGONISM BY NALMEFENE AND NALOXONE IN THE DOG - AN INTEGRATED PHARMACOKINETIC-PHARMACODYNAMIC COMPARISON

A continuous fentanyl infusion was administered to eight adult, male b eagle dogs for a duration of similar to 400 min at a rate of 30 mu g/k g/h. The extent of respiratory depression was quantified by continuous , noninvasive, transcutaneous pCO(2) recordings. Upon reaching a pseud o-steady-state of respiratory depression at similar to 120 min of fent anyl infusion, the animals then received, in a 2x2 crossover fashion s eparated by similar to 3 weeks, 30-minute equiefficacious infusions of nalmefene (12 mu g/kg/h) or naloxone (48 mu g/kg/h). Multiple venous blood samples were taken throughout the dosing regimen, and the result ing fentanyl, nalmefene, or naloxone plasma concentrations were determ ined. The concentration-time data were analyzed by noncompartmental me thods and subsequently linked to the pharmacodynamic effect data by a competitive antagonism link model. Separately, the biophase concentrat ions were linked to the plasma concentration-time profiles through a s ingle-exponential conduction function. The various pharmacokinetic/pha rmacodynamic parameters resulting from this semiparametric analysis we re analyzed by ANOVA, using a statistical model that considers carryov er effects. The results of these analyses indicate that several pharma cokinetic/pharmacodynamic parameters of the two antagonists were compa rable. However, nalmefene had a significantly more protracted terminal disposition and a significantly greater persistency in the biophase e valuated over the experimental time frame from 0 to 450 min.