Date of Award

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

First Advisor

David Taft

Committee Chair and Members

David Taft, Chair

Robert Bellantone

Kevin Sweeney

Akm Khairuzzaman

Keywords

Fentanyl, Fentanyl overdose, Intranasal naloxone, Naloxone, Opioid overdose, PBPK modeling of naloxone

Abstract

The therapeutic and nontherapeutic use of potent opioid agonists has increased dramatically over the past 20 years, with overdose trends following suit. Currently, naloxone is the primary drug used for treating emergency rescue from an opioid overdose. Naloxone works by displacing opioid agonists that are bound to receptors such as the μ-opioid receptor (MOR) in the brain, which are thought to be the sites of action responsible for symptoms due to overdosing, such as respiratory depression.

Intranasal (IN) administration of naloxone is an excellent alternative to the invasiveness of injections and poorly bioavailable oral formulation. However, the exact mechanism of how the drug enters the brain and how it produces its pharmacological response is not well-studied. While pharmacokinetic (PK) and pharmacodynamic (PD) data are available regarding the efficacy of naloxone in the reversal of prescription opioid overdose, their detailed mechanism in humans is not quantitatively fully understood. Also, there is very little research on IN naloxone PK and its application to the reversal of illicit high-potency synthetic opioids.

Taking advantage of drug transport to the brain by the IN route of administration requires a quantitative understanding of the general mechanisms and underlying processes for drug delivery to the brain. Modeling and studying IN naloxone administration can play an important role in future research by identifying appropriate dosing regimens for reversing different opioids and understanding the time course of respiratory depression recovery, as well as overcoming other side effects of opioids. It can also help to refine dosage regimens for special populations such as children and babies.

This project aims to build a physiologically based pharmacokinetic (PBPK) model describing naloxone disposition by IN and IV (intravenous) administration and evaluate the effects on displacement of opioid agonists. The goals were:

  • Evaluate the physiological factors affecting naloxone deposition from IV bolus (intravenous) and IN administration, and review and analyze published literature data for relevant pharmacokinetic information.
  • Develop a PBPK model for IV and IN naloxone delivery and disposition and numerically evaluate the systems of equations using the R programming language. The model included: 1) all relevant physiological compartments and processes; 2) pH, solubility, and partitioning considerations for naloxone (a weak base); and 3) interactions with MORs, including the rates and extents of binding and release.
  • Extend the naloxone PBPK model to simultaneously account for the disposition and displacement kinetics of an opioid agonist that is initially bound to the MORs, which would model naloxone rescue from an opioid overdose.
  • Simulate the effects of naloxone administration and deposition on the ensuing opioid agonist displacement and the resulting time course of pharmacological response vs. the agonist displacement time profile.
  • Simulate results for a target patient population using physiologically relevant parameter values.

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