Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : a study in healthy volunteers.
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 mu 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 mu receptor. For buprenorphine, the values of the rate constants of receptor association (k(on)) and dissociation (k(off)) were 0.203 mL/ng/min and 0.0172 min(-)(1), respectively. The value of the equilibrium dissociation constant (K(D)) was 0.18 nmol/L. The half-life (t((1/2))) 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.
Yassen
Ashraf
A
Division of Pharmacology, Leiden/Amsterdam Centre for Drug Research, Leiden, The Netherlands.
Olofsen
Erik
E
van Dorp
Eveline
E
Sarton
Elise
E
Teppema
Luc
L
Danhof
Meindert
M
Dahan
Albert
A
D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects; D002047:Buprenorphine / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D009270:Naloxone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012129:Respiratory Function Tests; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine