Current antiretroviral (ARV) medications for HIV treatment and prevention require lifelong daily dosing, which can lead to reduced patient adherence due to pill fatigue. This increases 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 have designed, synthesized, and evaluated emtricitabine (FTC) prodrugs that mask key hydrophilic groups and make these drugs compatible with SDN formulation approaches. Prodrug activation kinetics have been assessed under a variety of physiologically relevant conditions to mimic those encountered by the complete regimen administered via intramuscular depot. In addition, prodrugs have been analyzed for antiviral activity in cases where it is likely prodrugs will reach and undergo activation in target cells. The most promising candidates to emerge from these studies have been screened for generation of SDNs. Overall, this research is expected to accelerate the development of complete LA-ARV regimens to significantly improve adherence.  <br/>

Development of prodrug approaches for long-acting nanoformulations of emtricitabine-based regimens

254th National Meeting (2017)

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