Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose

Authors

• Hala Aldawod, University of the PacificFollow
• Arjun D. Patel, University of the Pacific
• Rasha Emara, University of the PacificFollow
• Dengpan Liang, University of the PacificFollow
• Joshua S. Ho, University of the Pacific
• Toufiq Ul Amin, University of the PacificFollow
• Md Tariqul Haque Tuhin, University of the PacificFollow
• Abdulmalek Balgoname, University of the PacificFollow
• Avishan Kiani, University of the PacificFollow
• Jumana M. Ajlouny, University of the Pacific
• Melanie A. Felmlee, University of the PacificFollow
• Miki S. Park, University of the PacificFollow
• Bhaskara R. Jasti, University of the PacificFollow
• William K. Chan, University of the PacificFollow
• James A, Uchizono, University of the PacificFollow
• Mamoun M. Alhamadsheh, University of the PacificFollow

Document Type

Article

Publication Title

Nature Communications

Department

Pharmacy

ISSN

20411723

Volume

16

Issue

1

DOI

10.1038/s41467-025-55945-4

First Page

1

Last Page

18

Publication Date

1-23-2025

Abstract

The opioid crisis, driven by synthetic opioids like fentanyl, demands innovative solutions. The opioid antidote naloxone has a short action (~ 1 hour), requiring repeated doses. To address this, we present a new and simple naloxone prodrug delivery system repurposing a hydrophilic derivative of acoramidis, a potent transthyretin ligand. When the fully soluble prodrug solution is administered subcutaneously, the prodrug forms a zwitterionic depot at physiological pH, enabling extended naloxone release. This non-polymeric depot-forming approach is rare and employs carboxylesterase 2 for selective bioactivation, ensuring controlled drug release. In male rats and cynomolgus monkeys, a single subcutaneous dose provides steady naloxone release over several days, reducing blood-brain barrier diffusion, withdrawal symptoms, and CNS toxicity. Preclinical studies demonstrated efficacy in rat overdose models and achieved monkey naloxone levels matching effective human therapeutic levels. Although monkey efficacy was not assessed, combined rat efficacy and monkey pharmacokinetics suggest strong potential for successful human translation.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Aldawod, Hala; Patel, Arjun D.; Emara, Rasha; Liang, Dengpan; Ho, Joshua S.; Amin, Toufiq Ul; Tuhin, Md Tariqul Haque; Balgoname, Abdulmalek; Kiani, Avishan; Ajlouny, Jumana M.; Felmlee, Melanie A.; Park, Miki S.; Jasti, Bhaskara R.; Chan, William K.; Uchizono, James A,; and Alhamadsheh, Mamoun M., "Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose" (2025). Pacific Faculty Work. 53.
https://scholarlycommons.pacific.edu/all-faculty/53