Clinical Study to Investigate the Pharmacokinetics of Multiple Repeated Doses of Intranasal Naloxone
Condition: Healthy Subjects; Opioid Antagonist; Pharmacokinetics
Study type: Interventional
Phase: Phase 1

Summary: 
      Intranasal (IN) naloxone is available as 2 mg or 4 mg dose with the indication to
      re-administer additional doses every 2 to 3 minutes (using alternating nostrils) if needed
      until emergency medical assistance arrives. The 4 mg dose is distributed in packages of two
      nasal sprays (1 dose per nasal spray), but additional doses can be administered if needed and
      available.

      While the pharmacokinetics of IN naloxone have been determined following administration of a
      4 mg dose in each nostril concurrently, the pharmacokinetics have not been determined
      following multiple doses when there is a 2-3 minute delay between doses and when doses are
      re-administered to the same nostril.

      Obtaining data with repeat dosing will inform if and how fast naloxone plasma concentrations
      can be reached to be able to reverse highly-potent opioid overdoses. This study will be a
      randomized, unblinded, three-way crossover study to determine naloxone plasma concentration
      after administration of multiple doses:

      A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes) B. Four 4 mg IN naloxone doses (2
      doses every 2.5 minutes) C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)
    

Detailed description: 
      Naloxone, a fast-acting mu-opioid antagonist, is a treatment commonly used in reversing
      opioid overdose. Naloxone is available in multiple formulations, including for injection
      intravenously, intramuscularly or subcutaneously, and more recently as a spray administered
      intranasally (IN). The IN naloxone formulation, which was approved in 2015, is of particular
      interest as there is a need for naloxone formulations for community use by caregivers and
      first responders/law enforcement who do not have medical training. It is critical to
      administer naloxone as quickly as possible to prevent irreversible brain damage and death.

      The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER),
      Division of Applied Regulatory Science (DARS) has conducted modeling and simulation,
      evaluating how many doses of IN naloxone may be needed to reverse opioid-induced respiratory
      depression from fentanyl and fentanyl derivates under a range of overdose scenarios. These
      analyses have suggested that more than two doses of IN naloxone are sometimes required to
      reverse the effects of highly potent opioids (e.g., certain fentanyl derivatives). Experience
      with intranasal formulations for other products has shown that repeat administration of doses
      given in close proximity to the same nostril can influence drug exposure due to run-off from
      the application site, limited absorption, or other factors. While the pharmacokinetics of IN
      naloxone have been determined following administration of a 4 mg dose in each nostril
      concurrently, the pharmacokinetics have not been determined following multiple doses
      according to the FDA product label:

        -  Administer a single spray intranasally into one nostril.

        -  Administer additional doses using a new nasal spray with each dose, if the patient does
           not respond or responds and then relapses into respiratory depression, additional doses
           may be given every 2 to 3 minutes until emergency medical assistance arrives.

      This involves a 2-3 minute delay between each dose and re-administering to a previously dosed
      nostril starting with the 3rd dose, which may result in a less than dose-proportional
      increase in naloxone plasma concentration and/or delayed increase in naloxone exposure
      compared to the first 2 doses. Obtaining data with repeat dosing will inform if and how fast
      naloxone plasma concentrations can be reached to be able to reverse highly-potent opioid
      overdoses.

      This study will be a randomized, unblinded, three-way crossover study to determine naloxone
      plasma concentration after administration of multiple doses:

      A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes) B. Four 4 mg IN naloxone doses (2
      doses every 2.5 minutes) C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)

      The above 3 treatments will be evaluated in a randomized order over 3 treatment periods.
      Healthy subjects will be randomized to one of six treatment sequences (i.e., ABC, ACB, BAC,
      BCA, CAB, CBA). Subjects will report to the study site for screening from Days -28 to -2 and
      then will return to the site on Day -1 for baseline assessments and check-in. After check-in
      (Day -1), subjects will receive dosing for the 3 respective treatment periods on Days 1, 4
      and 7. There will be two days of washout between each treatment period. Participants will be
      confined in the study clinic from Day -1 until the morning of Day 8. On dosing days, dosing
      will occur as per the treatment description and pharmacokinetic (PK) assessments will occur
      at 16 different time points.
    

Intervention name(s): Four naloxone nasal spray doses (1 every 2.5 min); Four naloxone nasal spray doses (2 every 2.5 min); Two naloxone nasal spray doses (1 every 2.5 min)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min; Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min); Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Other intervention name(s): Narcan nasal spray; Narcan nasal spray; Narcan nasal spray
Intervention MeSH terms: Naloxone
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This is a three-way crossover study where subjects will be randomized to one of six possible treatment sequences.
Masking: None (Open Label)
Primary purpose: Other
Keywords: Opioid antagonist; Intranasal naloxone; Pharmacokinetics