NCT06306391

Pharmacokinetics of Intravenous and Intranasal Formulations of Naloxone in Healthy Volunteers.

Physiologically Based Pharmacokinetic Modelling of Intravenous and Intranasal Formulations of Naloxone in Healthy Volunteers.

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 8 (actual)
• Sponsor: Parc de Salut Mar · Academic / Other
• Sex: All
• Age: 18 Years – 55 Years
• Healthy volunteers: Accepted

Summary

This is a phase I interventional clinical trial and the aim will be to characterize the PK and PD of two formulations of naloxone (intranasal and intravenous) in healthy subjects, which will be used to verify/validate nasal-CNS-PBPK (Physiologically Based Pharmacokinetic) model predictions following intranasal dosing.

Detailed description

Naloxone is a semisynthetic morphine derivative and is a specific opioid antagonist that acts competitively at opioid receptors. It reveals very high affinity for the opioid receptor sites. Naloxone does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists. In the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical or mental dependence. Intranasally administered naloxone has been demonstrated to be rapidly absorbed, as evidenced by very early appearance (as early as 1 minute after administration) of the active substance in systemic circulation. A study investigating intranasal naloxone (Nyxoid™) at doses of 1, 2, 4 mg (MR903-1501) shows that the median (range) tmax associated with intranasal administration of naloxone was 15 (10, 60) minutes for 1 mg, 30 (8, 60) minutes for 2 mg and 15 (10, 60) minutes for 4 mg intranasal doses. Onset of action following intranasal administration can reasonably be expected to occur in each individual before the tmax is reached. The half value duration (HVD) for intranasal administration were longer than for intramuscular administration (intranasal, 2 mg, 1.27h, intramuscular, 0.4 mg, 1.09h) from which we can infer a longer duration of action of naloxone given by the intranasal rather than the intramuscular route. The overall aim is to develop a physiologically based pharmacokinetic (PBPK) model for drug release, disposition and dissolution following intranasal drug delivery. Following delivery, drug release from the formulations and disposition in the nasal cavity will be described. The model will also account for drug transport through epithelial tissue and mucociliary clearance. Predicted local brain and systemic PK will therefore be linked to drug release, dissolution, and disposition in the brain and the rest of the body. In vitro permeability, transporter kinetic and proteomics data from the olfactory region, as well as published clinical data following intravenous and intranasal delivery will be used to support this. Integration of all these processes in a dynamic model will help to disentangle different kinetic process which contribute to this complex system, which will help us to explore the interplay between various processes. Intranasal: 1.8 mg nasal spray, solution in single-dose container. Intravenous: 1 mg in total (from 0.4 mg/mL injectable solution) Doses selected, in the low range of those tested previously in clinical opioid overdose situations, were already tested experimentally in a bioavailability study in healthy subjects comparing the two routes of administration of naloxone that will be evaluated in the protocol.

Conditions

• Healthy

Interventions

Type	Name	Description
DRUG	Intravenous naloxone	Nyoxid 1.8 mg nasal spray, solution in single-dose container. Study drugs (naloxone nasal spray and naloxone intravenously) will be administered in 8 subjects in two sequences in fasting conditions (10 hours pre-dose and 4 hours post dose): Intranasal -\> washout period -\>intravenous (n=4) and Intravenous -\>washout period -\> intranasal (n=4).
DRUG	Intranasal naloxone	Naloxone Kern Pharma 1 mg in total (from 0.4 mg/mL injectable solution). Study drugs (naloxone nasal spray and naloxone intravenously) will be administered in 8 subjects in two sequences in fasting conditions (10 hours pre-dose and 4 hours post dose): Intranasal -\> washout period -\>intravenous (n=4) and Intravenous -\>washout period -\> intranasal (n=4).

Timeline

• Start date: 2024-03-05
• Primary completion: 2024-05-13
• Completion: 2024-09-02
• First posted: 2024-03-12
• Last updated: 2025-08-05

Locations

2 sites across 1 country: Spain