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 À1). 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 e32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively. Conclusions: A parentemetabolite 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.

Opioid Overdose: Limitations in Naloxone Reversal of Respiratory Depression and Prevention of Cardiac Arrest

“…Typical model parameter estimates were an elimination clearance of 3.5 l/min (in a 70-kg individual) and volume of distribution of 1.6 to 1.8 l/kg. 15,16 Similar elimination clearance estimates were later observed when studying high-dose naloxone (3.4 l/ min) but with a somewhat greater volume of distribution (2.7 l/kg), 17 which may be explained by differences in naloxone sampling schemes. An important model parameter derived from pharmacokinetic or pharmacodynamic data analysis is parameter t½k e0 (= ln2/k e0 ) which is the arterial blood to effect-site equilibration half-life.…”

“…µ-Opioid receptor Affinities and receptor Dissociation Constants of Different Opioids6,15,[17][18][19] …”

Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters

“… Key elimination pathways of commonly co-prescribed medications * [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. ( A ) Location of drug-metabolizing enzymes and transporters of interest.…”

Population pharmacokinetics of buprenorphine and naloxone sublingual combination in Chinese healthy volunteers and patients with opioid use disorder: Model-based dose optimization

“…Results from previous studies and exploratory analyses ( Supplementary Figure S5 ) support one-, two- and three-compartment models with first-order absorption and first-order elimination as candidate structural models ( Yassen et al, 2007 ; Dowling et al, 2008 ; Papathanasiou et al, 2019 ; Skulberg et al, 2019 ). The code of final model can be found in Supplementary Material .…”