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Long Duration, Novel Opioid Medical Countermeasure for Intramuscular Injection

Description:

TECHNOLOGY AREA(S): Chem Bio_defensebio Medical 

OBJECTIVE: To develop a stable, intermuscular (IM) formulated drug product for a long duration opioid antagonist, or novel opioid medical countermeasures (MCM) (e.g., respiratory stimulants, non-µ-opioid receptor MCMs) to provide both immediate relief from opioid poisoning, as well as prolonged protection from re-intoxication. The drug product is intended for use by U. S. Department of Defense (DoD) Service Members in far-forward deployed settings and must be an effective and suitable long duration rescue therapy for opioid casualties. 

DESCRIPTION: The DoD seeks to develop and field medical countermeasures to treat the toxic symptoms following opioid poisoning. The high availability of synthetic opioids, such as fentanyl and its derivatives, is a threat to both the civilian and military communities [1-4]. The rapid onset of respiratory depression creates a critical need to quickly administer adequate doses of MCM to immediately reverse adverse effects. Furthermore, it would be advantageous to field an MCM with a sustained efficacy profile to either: 1) provide protection against opioid toxicity greater than 8 hours; 2) allow time for evacuation of a casualty to definitive care, usually within 1 to 2 hours without the chance of renarcotization; or 3) eliminate the need for evacuation [5-9]. Commercially available naloxone products, 2 mg EVZIO® autoinjector and 4 mg Narcan® (naloxone) nasal spray, are effective for immediate rescue from respiratory depression. However, naloxone’s half-life that is shorter than the duration of action of many opioids, including carfentanil. This results in the need for additional doses of naloxone due to renarcotization [1, 6, 7, 9]. Naloxone’s short half-life makes it desirable to develop and field a MCM in an autoinjector with either a longer duration of action or one that uses a mechanism other than µ-opioid receptor antagonism to counteract opioid poisoning. Currently, long acting opioid antagonists are available; however, there are none available in cGMP formulations suitable for IM injection. The DoD is also interested in novel opioid MCMs such as respiratory stimulants (e.g., ampakines) and non-µ opioid receptor MCMs that would allow for use of current opioid pain management protocols. The rapid delivery of long acting opioid antagonists or other novel opioid MCMs is paramount for soldiers to remain ambulatory to complete the mission or move though a clean/dirty line for transition to a higher echelon of medical care. An opioid casualty encountered during DoD and Joint Forces missions will differ from casualties encountered by civilian emergency response teams. Civilian first responders primarily treat opioid overdoses in diverse populations with co-morbidities. They are concerned with precipitating withdrawal symptoms following naloxone treatment. Conversely, in the DoD and the Joint Services, the MCM will be administered to non-opioid dependent, healthy individuals with few or no underlying medical conditions. As such, safe administration of high doses of opioid antagonists with low regret may be readily performed in military settings. On a battlefield, the capability for IM delivery of an immediately acting opioid antagonist followed by a longer acting MCM could be lifesaving and mission essential. The goal is to eventually deliver these treatments via an autoinjector device. This topic seeks to develop a rescue therapeutic for IM administration that provides a longer duration or improved capability over naloxone products. The MCM could be a novel opioid antagonist, target a non-µ opioid receptor, or work by a novel mechanism. IM administration is the preferred route of administration. The medical countermeasures are intended to be delivered as self- and buddy-aid, as well as at higher roles of care (i.e., hospital). The drug product should be stable and suitable for use across a wide range of temperatures in operationally relevant environmental conditions. The drug product should be administered by trained personnel with little effort and low operational and logistical burden. The drug product will require Food and Drug Administration (FDA) approval/licensure, as will the combination drug-device delivery system. This award mechanism will bridge the gap between laboratory-scale innovation and entry into a recognized FDA regulatory pathway leading to commercialization and eventual combination with an autoinjector. 

PHASE I: Establish preliminary specifications of the opioid medical countermeasure for both immediate effect and extended release/longer duration formulations or drug. Predict human MCM dosages for IM administration that would result in efficacious blood levels within 3 – 5 minutes and sustained levels for a minimum of 8-hours. The desired final volume is to be no more than 2.0 mL. In vitro binding studies with multiple opioid receptor subtypes and other preliminary in vitro study design(s) for efficacy are desired. No animal use is permitted during this proof-of-concept/feasibility phase. 

PHASE II: Evaluate the candidate drug product for performance and conduct of early animal trials. Evaluation should include detailed characterization of performance of IM injection in a suitable animal model, demonstrate in vivo efficacy against opioid poisoning, and conduct toxicology and safety studies required to support an IND, 510(k), or related FDA filing. Conduct early formulation stability assessments for chemical degradation and at operationally relevant temperature conditions. The objective is to achieve at least two-year stability at room temperature. Initiate pharmacokinetic (PK) studies of the optimized formulation prototype or drug in relevant animal models. The objective is to determine the plasma levels of the drug after a single IM injection and determine the Cmax and the AUCtotal, Tmax and the elimination half-life (EC50). Considerations for how the drug product will be manufactured consistent with FDA guidelines and amenable to industry best practices (e.g., cGMP and ISO13485:2016) should be documented. 

PHASE III: PHASE III: The small business firm with an appropriate partner will complete non-clinical and IND enabling studies initiated in Phase II and conduct human Phase 1 clinical trials to establish human safety and obtain pharmacokinetic performance data. PHASE III DUAL USE APPLICATIONS: A full spectrum opioid MCM formulation could be utilized by medical professionals, law enforcement agents, and first responders to reduce toxicity and mortality of opioid poisoning. For example, law enforcement agents or first responders, a population which presumably is also non-opioid dependent, could use the medical countermeasure upon accidental exposure to opioids. 

REFERENCES: 

1: World Health Organization, Expert Committee on Drug Dependence 39th Meeting. Carfentanil: Critical Review Report. Agenda item 4.8. 6-10 November 2017.

2:  NDEWS. Special Report: Fentanyl and fentanyl analog: National drug early warning system (NDEWS)

3:  2015 [updated December 7 2015].

4:  Kinetz E, Satter R. Ohio is hardest hit by Chinese carfentanil trade, logging 343 of more than 400 seizures in US. Associated Press. November 3, 2016. http:// http://www.ohio.com/news/local/ohio-is-hardest-hit-by-chinese-carfentanil-trade-logging-343-of-more-than-400-seizures-in-u-s-1.724486. Accessed February 10, 2017.

5:  Sutter ME, Gerona RR, Davis MT, Roche BM, Colby DK, Chenoweth JA, Adams AJ, Owen KP, Ford JB, Black HB, Albertson TE. Fata fentanyl: One pill can kill. Academic Emergency Medicine. 2017

6:  24(1) 106-113.

7:  Drug Enforcement Agency (DEA). Fentanyl. A briefing guide for first responders. 2017. Available from: https://www.dea.gov/druginfo/Fentanyl_BriefingGuideforFirstResponders_June2017.pdf

8:  Faul M, Lurie P, Kinsman JM, Dailey MW, Carbaugh C, Sasser SM. Multiple naloxone administrations among emergency medical service providers is increasing. Prehospital Emergency Care. 2017

9:  21(4): 411-419.

10:  Somerville MJ, O’Donnell J, Gladden RM, Zibbell JE, Green TC, Younkin M, Ruiz S, Babakhanlou-Chase H, Chan M, Callis BP, Kuramoto-Crawford J, Nields HM, Walley AY. Characteristics of fentanyl overdose – Massachusetts, 2014-2016. Morbidity and Mortality Weekly Report. April 14, 2017

11:  66(14): 382-386.

12:  Mundin G, McDonald R, Smith K, Harris S, Strang J. Pharmacokinetics of concentrated naloxone nasal spray over first 30 minutes post-dosing: Analysis of suitability for opioid overdose reversal. Addiction. 2017

13:  112:1647-1652.

14:  FDA Advisory Committee on the Most Appropriate Dose or Doses of Naloxone to Reverse the Effects of Life-threatening Opioid Overdose in the Community Settings. Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee on October 5, 2016.

KEYWORDS: Opioids, Autoinjector, High Dose Naloxone, Medical, Countermeasure, Drug-delivery, µ Opioid Receptor Antagonist 

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