Whole Body PBPK Model of Nasal Naloxone Administration to Measure Repeat Dosing Requirements During Fentanyl Overdose

Opioid use in the United States and abroad is an endemic part of culture with yearly increases in overdose rates and deaths. As rates of overdose incidence increases, the use of the safe and effective reversal agent, naloxone, in the form of a nasal rescue spray is being fielded and used by emergency medical technicians (EMTs) at a greater and greater rate. Despite advances in deployment of these rescue products, deaths are continuing to increase. There is evidence that repeated dosing of a naloxone nasal spray (such as Narcan) is becoming more common due to the amount and type of opiate being abused. Despite the benefits of naloxone related to opioid reversals, we lack repeated dosing guidelines as a function of opiate and amount the patient has taken. Goal directed dosing is promising, where respiratory markers are being used as an indication of the patient recovery but require time and understanding by the EMT. We construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdoses. We demonstrate that naloxone is highly effective at reversing respiratory symptoms of the patient and recommend dosing requirements as a function of opiate amount administered. By designing the model to include circulation and respiration we investigate physiological markers that may be used in goal directed therapy rescue treatments.