High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.

Theodoros Papathanasiou; Anders Springborg; Kenneth Thermann Kongstad; Dan Stærk; Kirsten Møller; Bradley K. Taylor; Trine Meldgaard Lund; Mads U. Werner

doi:10.1016/j.bja.2018.12.007

High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.

Theodoros Papathanasiou, Anders Springborg, Kenneth Thermann Kongstad, Dan Stærk, Kirsten Møller, Bradley K. Taylor, Trine Meldgaard Lund, Mads U. Werner

6 Citationer (Scopus)

Abstract

Background: Naloxone, 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. Methods: Eight 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. Results: Three- 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. Conclusions: A 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 registration: NCT01992146.

Originalsprog	Engelsk
Tidsskrift	British Journal of Anaesthesia
Vol/bind	123
Sider (fra-til)	e204-e214
ISSN	0007-0912
DOI	https://doi.org/10.1016/j.bja.2018.12.007
Status	Udgivet - aug. 2019

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10.1016/j.bja.2018.12.007

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title = "High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.",

abstract = "Background: Naloxone, 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. Methods: Eight 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. Results: Three- 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. Conclusions: A 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 registration: NCT01992146.",

author = "Theodoros Papathanasiou and Anders Springborg and Kongstad, {Kenneth Thermann} and Dan St{\ae}rk and Kirsten M{\o}ller and Taylor, {Bradley K.} and Lund, {Trine Meldgaard} and Werner, {Mads U.}",

year = "2019",

month = aug,

doi = "10.1016/j.bja.2018.12.007",

language = "English",

volume = "123",

pages = "e204--e214",

journal = "British Journal of Anaesthesia",

issn = "0007-0912",

publisher = "Oxford University Press",

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TY - JOUR

T1 - High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.

AU - Papathanasiou, Theodoros

AU - Springborg, Anders

AU - Kongstad, Kenneth Thermann

AU - Stærk, Dan

AU - Møller, Kirsten

AU - Taylor, Bradley K.

AU - Lund, Trine Meldgaard

AU - Werner, Mads U.

PY - 2019/8

Y1 - 2019/8

N2 - Background: Naloxone, 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. Methods: Eight 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. Results: Three- 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. Conclusions: A 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 registration: NCT01992146.

AB - Background: Naloxone, 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. Methods: Eight 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. Results: Three- 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. Conclusions: A 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 registration: NCT01992146.

U2 - 10.1016/j.bja.2018.12.007

DO - 10.1016/j.bja.2018.12.007

M3 - Journal article

C2 - 30915992

SN - 0007-0912

VL - 123

SP - e204-e214

JO - British Journal of Anaesthesia

JF - British Journal of Anaesthesia

ER -

High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.

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