Creation of a long-acting rilpivirine prodrug nanoformulation

James R. Hilaire, Aditya N. Bade, Brady Sillman, Nagsen Gautam, Jonathan Herskovitz, Bhagya Laxmi Dyavar Shetty, Melinda S. Wojtkiewicz, Adam Szlachetka, Benjamin G. Lamberty, Sruthi Sravanam, Howard S. Fox, Yazen Alnouti, Prasanta K. Dash, Jo Ellyn M. McMillan, Benson J. Edagwa, Howard E. Gendelman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25 weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug half-life and improve tissue biodistribution. These results warrant further development for human use.

Original languageEnglish (US)
Pages (from-to)201-211
Number of pages11
JournalJournal of Controlled Release
Volume311-312
DOIs
StatePublished - Oct 2019

Fingerprint

Rilpivirine
Prodrugs
Pharmaceutical Preparations
Half-Life
Therapeutics
Drug Compounding
Injections
Intramuscular Injections
Human Development
Tissue Distribution
Libraries
Quality of Life
Clinical Trials

Keywords

  • Antiretroviral therapy
  • Long-acting slow effective release antiretroviral therapy
  • Monocyte-derived macrophages
  • Nanoformulation
  • Prodrugs
  • Rilpivirine

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Hilaire, J. R., Bade, A. N., Sillman, B., Gautam, N., Herskovitz, J., Dyavar Shetty, B. L., ... Gendelman, H. E. (2019). Creation of a long-acting rilpivirine prodrug nanoformulation. Journal of Controlled Release, 311-312, 201-211. https://doi.org/10.1016/j.jconrel.2019.09.001

Creation of a long-acting rilpivirine prodrug nanoformulation. / Hilaire, James R.; Bade, Aditya N.; Sillman, Brady; Gautam, Nagsen; Herskovitz, Jonathan; Dyavar Shetty, Bhagya Laxmi; Wojtkiewicz, Melinda S.; Szlachetka, Adam; Lamberty, Benjamin G.; Sravanam, Sruthi; Fox, Howard S.; Alnouti, Yazen; Dash, Prasanta K.; McMillan, Jo Ellyn M.; Edagwa, Benson J.; Gendelman, Howard E.

In: Journal of Controlled Release, Vol. 311-312, 10.2019, p. 201-211.

Research output: Contribution to journalArticle

Hilaire, JR, Bade, AN, Sillman, B, Gautam, N, Herskovitz, J, Dyavar Shetty, BL, Wojtkiewicz, MS, Szlachetka, A, Lamberty, BG, Sravanam, S, Fox, HS, Alnouti, Y, Dash, PK, McMillan, JEM, Edagwa, BJ & Gendelman, HE 2019, 'Creation of a long-acting rilpivirine prodrug nanoformulation', Journal of Controlled Release, vol. 311-312, pp. 201-211. https://doi.org/10.1016/j.jconrel.2019.09.001
Hilaire JR, Bade AN, Sillman B, Gautam N, Herskovitz J, Dyavar Shetty BL et al. Creation of a long-acting rilpivirine prodrug nanoformulation. Journal of Controlled Release. 2019 Oct;311-312:201-211. https://doi.org/10.1016/j.jconrel.2019.09.001
Hilaire, James R. ; Bade, Aditya N. ; Sillman, Brady ; Gautam, Nagsen ; Herskovitz, Jonathan ; Dyavar Shetty, Bhagya Laxmi ; Wojtkiewicz, Melinda S. ; Szlachetka, Adam ; Lamberty, Benjamin G. ; Sravanam, Sruthi ; Fox, Howard S. ; Alnouti, Yazen ; Dash, Prasanta K. ; McMillan, Jo Ellyn M. ; Edagwa, Benson J. ; Gendelman, Howard E. / Creation of a long-acting rilpivirine prodrug nanoformulation. In: Journal of Controlled Release. 2019 ; Vol. 311-312. pp. 201-211.
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AU - Herskovitz, Jonathan

AU - Dyavar Shetty, Bhagya Laxmi

AU - Wojtkiewicz, Melinda S.

AU - Szlachetka, Adam

AU - Lamberty, Benjamin G.

AU - Sravanam, Sruthi

AU - Fox, Howard S.

AU - Alnouti, Yazen

AU - Dash, Prasanta K.

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AU - Edagwa, Benson J.

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