Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory-Depressant Effect of Buprenorphine and Fentanyl in Rats

Abstract

The purpose of this investigation was to develop a mechanismbased pharmacokinetic/pharmacodynamic (PK/PD) model to predict the time course of respiratory depression following administration of opioids in rats. The proposed model is based on receptor theory and aims at the separate characterization of biophase distribution and receptor association/dissociation kinetics as determinants of hysteresis between plasma concentration and effect. Individual concentration time courses of buprenorphine and fentanyl were determined in conjunction with continuous monitoring of respiratory depression. Buprenorphine and fentanyl were administered intravenously in various doses. For buprenorphine hysteresis was best described by a combined biophase distribution-receptor association/dissociation model with a linear transducer function. The values of the parameter estimates of the rate constants for biophase distribution (k eo ), receptor association (k on ), and dissociation (k off ) were 0.0348 min Ϫ1 [95% confidence interval (CI), 0.0193-0.0503 min Ϫ1 ], 0.57 ml/ng/min (95% CI, 0.38 -0.76 ml/ng/min), and 0.0903 min Ϫ1 (95% CI, 0.035-0.196 min Ϫ1 ), respectively. The values of the equilibrium dissociation constant and intrinsic activity were 0.16 ng/ml and 0.48 (95% CI, 0.45-0.51), respectively. The value of the K d is close to reported estimates of receptor affinity in vitro confirming the validity of the mechanism-based PK/PD model. For fentanyl, unrealistically high estimates of the rate constants for receptor association and dissociation were obtained, indicating that hysteresis is caused solely by biophase distribution kinetics. This is consistent with fentanyl's fast receptor association/ dissociation kinetics in vitro. As a result, the mechanism-based PK/PD model of fentanyl could be reduced to a biophase distribution model with fractional sigmoid E max pharmacodynamic model.

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

“…By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.Recently, the pharmacokinetic-pharmacodynamic (PK-PD) relationship of buprenorphine for the effect on the respiratory response has been studied in rats and humans (Yassen et al, 2007). In these investigations, buprenorphine has been shown to display ceiling of the respiratory depressant effect, indicating that buprenorphine acts functionally as a partial agonist at the -opioid receptor.…”

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

“…Based on weight these doses are more than 10-fold larger than in humans (117,378,772). However, the resultant effect-site concentrations between these two mammalian species appear to differ by less than an order of magnitude.…”

“…In addition to measurement limitations, pharmacokinetics and pharmacodynamics seem to differ significantly between species for both intravenous anesthetics and opioids and seem subject to allometry (378). As a result, rodents (rats and mice) and other small mammals (rabbits) require much larger single doses (mg/kg) and infusion rates (mg/kg/h) of intravenous agents (61,482,491) and opioids (microgram/kg) (25,117,314,359,361,436,772,774) on a weight basis than larger mammals (dogs) and primates (humans). Finally, it is important to realize that only the free plasma concentrations in the aqueous phase of intravenous anesthetics or opioids seem to be relevant for the clinical effect, not the total plasma concentration.…”

“…In these in vitro preparations various bath concentrations of μ-opioid agonists have been used, ranging from 100 nM to more than 1 μM. Most of these opioid agonist concentrations are above the clinically relevant range of low nanomolar plasma concentrations that cause respiratory depression in humans (774) and rats (772) in vivo, and thus the results may not be directly applicable to the in vivo clinical scenario (see also Section "Opioid effects on respiratory neurons in vivo").…”

“…However, the resultant effect-site concentrations between these two mammalian species appear to differ by less than an order of magnitude. For example, the EC50 of fentanyl for respiratory depression in rats during 6.5% inspired CO 2 is 4.83 ng/mL (14.4 nM) (for details see figure 7 in Yassen 2006) (772). Additional studies by Yassen et al suggest that the EC50 of fentanyl for respiratory depression in humans is about four times less, that is, 1.14 ng/mL (3.4 nM) (774) (see Section on Fentanyl, subsection on "Effects on the hypercapnic ventilatory response").…”