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

A Study in Healthy Volunteers

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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.

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Acknowledgements

This study was supported in part by Grünenthal GmbH (Aachen, Germany). The authors have no potential conflicts of interest that are relevant to the content of the study.

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Authors and Affiliations

  1. Division of Pharmacology, Leiden/Amsterdam Centre for Drug Research, Leiden, The Netherlands

    Ashraf Yassen &  Meindert Danhof

  2. Department of Anesthesiology, Leiden University Medical Centre, Leiden, The Netherlands

    Erik Olofsen, Eveline van Dorp, Elise Sarton, Luc Teppema & Albert Dahan

  3. LAP&P Consultants BV, Leiden, The Netherlands

    Meindert Danhof

Authors
  1. Ashraf Yassen
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  2. Erik Olofsen
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  3. Eveline van Dorp
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  4. Elise Sarton
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  5. Luc Teppema
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  6. Meindert Danhof
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  7. Albert Dahan
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Correspondence to Meindert Danhof.

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Yassen, A., Olofsen, E., van Dorp, E. et al. Mechanism-Based Pharmacokinetic-Pharmacodynamic Modelling of the Reversal of Buprenorphine-Induced Respiratory Depression by Naloxone. Clin Pharmacokinet 46, 965–980 (2007). https://doi.org/10.2165/00003088-200746110-00004

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  • DOI: https://doi.org/10.2165/00003088-200746110-00004

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