Radiation Biology

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SU_39_2393 - Ionizing Irradiation Mitigator GS-nitroxide (JP4-039) is Deliverable in an I.M. Formulation Suitable for Self-Administration

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Ionizing Irradiation Mitigator GS-nitroxide (JP4-039) is Deliverable in an I.M. Formulation Suitable for Self-Administration
M. Epperly1, P. Wipf2, R. Fisher2, and J. S. Greenberger3; 1UPMC Hillman Cancer Center, Pittsburgh, PA, 2University of Pittsburgh, Pittsburgh, PA, 3UPMC-Shadyside Hospital, Pittsburgh, PA

Purpose/Objective(s): Effective mitigation of ionizing irradiation toxicity in the civilian or military setting must be rapidly deployable in a formulation suitable for self-administration. The mitochondrial targeted GS-nitroxide (JP4-039) has been demonstrated to be highly effective in total body irradiation (TBI) mitigation in animal models (Rwigema, IJROBP, 80(3): 860-869, 2011, Goff, In Vivo, 25: 315-324, 2011, Steinman, Radiation Research, 189(1): 68-83, 2018), and is effective when delivered as late as 72 h after TBI. The drug has been shown to mitigate ionizing irradiation damage to the bone marrow and the gastrointestinal tract, and it is effective in organ specific (partial body) irradiation protection and mitigation (Berhane, Radiation Research, 182: 35-49, 2014, Shinde, Radiation Research, 185: 134-150, 2016). JP4-039 has also been shown to be effective for mitigation and treatment of beta irradiation (fallout) skin damage (Brand, J Investigative Derm, 137(3): 576-586, 2017). Pharmacokinetics (PK) experiments demonstrated clearance of JP4-039 after I.V. administration with a half-life of 10 min when administered I.V. (Christner, J Pharm & Biomed Analysis, S0731-7085(17): 32605-5, 2017).

Materials/Methods: We evaluated the feasibility of intra-muscular injection of JP4-039 in each of three commercially available formulations (Captisol, 2-hydroxypropyl-B-cyclodextrin (Cyclodextrin), and Miglyol-812-N). C57BL/6J male and female mice received the LD50/30 TBI dose of 9.25 Gy, and 24 h later were administered 10 mg/kg JP4-039 in 100 µmL I.M. formulation.

Results: Significant radiation mitigation was demonstrated when JP4-039 was administered in each formulation (Table) (n=12 per group). There was no significant mitigation seen in mice given each formulation alone (n=12 per group).
Survival Increase After Total Body Irradiation (TBI)
Formulation LD50/30 Survival Increase at Day 30 After 9.25 Gy
Miglyol-812-N/JP4-039 p = 0.0088
Cyclodextrin/JP4-039 p = 0.0015
Captisol/JP4-039 p = 0.0247

Conclusion: Satisfactory stability of JP4-039 in the most straightforward formulation using Miglyol-812-N was observed at room temperature, and this must now be assessed over a wide range of temperatures and storage intervals. The effectiveness in I.M. administration makes JP4-039 suitable for both civilian and military applications.

Author Disclosure: M. Epperly: None. P. Wipf: None. R. Fisher: None. J.S. Greenberger: None.

Michael Epperly, PhD

University of Pittsburgh Cancer Institute

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