• Theodoros Papathanasiou, Anders Deichmann Springborg, Kenneth Thermann Kongstad, Dan Staerk, Kirsten Møller, Bradley Kenneth Taylor, Trine Meldgaard Lund, and Mads Utke Werner.
• Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: theodoros.papathanasiou@sund.ku.dk.
• Br J Anaesth. 2019 Aug 1; 123 (2): e204-e214.

BackgroundNaloxone, an opioid receptor antagonist, is used as a pharmacological tool to detect tonic endogenous activation of opioid receptors in experimental pain models. We describe a pharmacokinetic model linking naloxone pharmacokinetics to its main metabolite after high-dose naloxone infusion.MethodsEight healthy volunteers received a three-stage stepwise high-dose i.v. naloxone infusion (total dose 3.25 mg kg-1). Naloxone and naloxone-3-glucuronide (N3G) plasma concentrations were sampled from infusion onset to 334 min after infusion discontinuation. Pharmacokinetic analysis was performed using non-linear mixed effect models (NONMEM). The predictive performances of Dowling's and Yassen's models were evaluated, and target-controlled infusion simulations were performed.ResultsThree- and two-compartment disposition models with linear elimination kinetics described the naloxone and N3G concentration time-courses, respectively. Two covariate models were developed: simple (weight proportional) and complex (with the shallow peripheral volume of distribution linearly increasing with body weight). The median prediction error (MDPE) and wobble for Dowling's model were -32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively.ConclusionsA parent-metabolite pharmacokinetic model was developed for naloxone and N3G after high-dose naloxone infusion. No saturable pharmacokinetics were observed. Whereas Dowling's model was inaccurate and over-predicted naloxone concentrations, Yassen's model accurately predicted naloxone pharmacokinetics. The newly developed covariate models may be used for high-dose TCI-naloxone for experimental and clinical practice.Clinical Trials RegistrationNCT01992146.Copyright © 2018 British Journal of Anaesthesia. All rights reserved.

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