Clinical Pharmacokinetics

, Volume 46, Issue 11, pp 965–980

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modelling of the Reversal of Buprenorphine-Induced Respiratory Depression by Naloxone

A Study in Healthy Volunteers

Authors

  • Ashraf Yassen
    • Division of PharmacologyLeiden/Amsterdam Centre for Drug Research
  • Erik Olofsen
    • Department of AnesthesiologyLeiden University Medical Centre
  • Eveline van Dorp
    • Department of AnesthesiologyLeiden University Medical Centre
  • Elise Sarton
    • Department of AnesthesiologyLeiden University Medical Centre
  • Luc Teppema
    • Department of AnesthesiologyLeiden University Medical Centre
    • Division of PharmacologyLeiden/Amsterdam Centre for Drug Research
    • LAP&P Consultants BV
  • Albert Dahan
    • Department of AnesthesiologyLeiden University Medical Centre
Original Research Article

DOI: 10.2165/00003088-200746110-00004

Cite this article as:
Yassen, A., Olofsen, E., van Dorp, E. et al. Clin Pharmacokinet (2007) 46: 965. doi:10.2165/00003088-200746110-00004
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Abstract

Background and objective

Respiratory depression is a potentially life-threatening adverse effect of opioid therapy. It has been postulated that the difficulty of reversing buprenorphine-induced respiratory depression is caused by slow receptor association-dissociation kinetics at the opioid μ receptor. The aim of this study was to characterise the pharmacodynamic interaction between buprenorphine and naloxone in healthy volunteers.

Methods

A competitive pharmacodynamic interaction model was proposed to describe and predict the time course of naloxone-induced reversal of respiratory depression. The model was identified using data from an adaptive naloxone dose-selection trial following intravenous administration of buprenorphine 0.2mg/70kg or 0.4mg/70kg.

Results

The pharmacokinetics of naloxone and buprenorphine were best described by a two-compartment model and a three-compartment model, respectively. A combined biophase equilibration-receptor association-dissociation pharmacodynamic model described the competitive interaction between buprenorphine and naloxone at the opioid μ receptor. For buprenorphine, the values of the rate constants of receptor association (kon) and dissociation (koff) were 0.203 mL/ng/min and 0.0172 min−1, respectively. The value of the equilibrium dissociation constant (KD) was 0.18 nmol/L. The half-life (t½) of biophase equilibration was 173 minutes. These estimates of the pharmacodynamic parameters are similar to values obtained in the absence of naloxone co-administration. For naloxone, the half-life of biophase distribution was 6.5 minutes.

Conclusions

Because of the slow receptor association-dissociation kinetics of buprenorphine in combination with the fast elimination kinetics of naloxone, naloxone is best administered as a continuous infusion for reversal of buprenorphine-induced respiratory depression.

Copyright information

© Adis Data Information BV 2007