Current antiretroviral (ARV) medications for HIV treatment and prevention require lifelong daily dosing, which can lead to reduced patient adherence due to pill fatigue, increasing the likelihood for treatment failure. Long-acting (LA) ARVs would allow less frequent administration, improving adherence. Despite success in the development of LA formulations for the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine and the integrase inhibitor cabotegravir, the nanomilling technologies used to produce them are incompatible with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) due to their high water solubility. Most current ARV combination therapies include administration of the NRTIs. Thus, in order to produce a complete LA dosing regimen, LA formulations of NRTIs are required. To enable the production of hydrophobic solid drug nanoparticles (SDNs), we propose the design, synthesis, and evaluation of a series of tunable emtricitabine (FTC) prodrugs that mask key hydrophilic groups and make these drugs compatible with SDN formulation approaches. Prodrug activation kinetics will be measured under a variety of physiologically relevant conditions to mimic those encountered by the complete regimen administered via intramuscular depot. In addition, prodrugs will be analyzed for lipophilicity and antiviral activity in cases where it is likely prodrugs will reach and undergo activation in target cells. The most promising candidates will be used to generate SDNs. The pharmacokinetic and efficacy benefits of these formulations will be tested with in vitro and in vivo model systems, guided by in silico physiologically-based pharmacokinetic modeling in collaboration with the University of Liverpool. Overall, this research is expected to accelerate the development of complete LA-ARV regimens to significantly improve adherence.

Public Health Relevance

Current antiretroviral (ARV) medications for the treatment and prevention of HIV infection require lifelong daily dosing. Over time, this can lead to reduced patient compliance, jeopardizing treatment efficacy. This research seeks to develop emtricitabine prodrugs that are amenable to nanoformulation, with the overall goal of producing a complete long-acting ARV regimen to help improve compliance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AI129549-01A1
Application #
9410823
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Protopopova, Marina N
Project Start
2017-05-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205