Development of Prodrug Approaches for Long‐Acting Nanoformulations of Emtricitabine‐Based Regimens

Most current antiretroviral (ARV) medications for HIV treatment and prevention necessitate lifelong daily dosing, and require high levels of patient adherence to be effective. Long‐acting injectable (LAI) ARVs would allow less frequent administration, improving adherence. Technologies currently used to produce LAI‐ARVs are incompatible with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) due to their high water solubility. It is critical to overcome this challenge to development of LAI NRTI strategies as most current ARV combination therapies include NRTI backbone therapies. We synthesized a series of carbamate‐based emtricitabine (FTC) prodrugs to increase hydrophobicity and improve compatibility for solid drug nanoparticle (SDN) formation. Prodrug activation kinetics were assessed in vitro via HPLC in human muscle, plasma, and liver fractions. Prodrugs were then screened for SDN compatibility using an emulsion templated/freeze drying method. Hits from these screens are defined by the following properties: Z‐average diameter <1000 nm, a polydispersity index of <0.5, and the ability to disperse in water at a concentration of 1 mg/mL. Prodrug release from SDNs and subsequent enzymatic conversion to FTC was quantified by HPLC in human muscle fractions in vitro . Carbamates bearing longer alkyl chains (C7 and C8) were most efficiently activated in all conditions. Hydrolysis rates in liver were higher than those in plasma or muscle. Carbonate moieties at the 5′‐position were hydrolyzed more efficiently than the carbamate moiety under all conditions. Nanoparticle screening at 10 wt% prodrug demonstrated a correlation between calculated logP and the number of hits obtained for carbamate/carbonate prodrugs (39/42), but not for carbamate‐only prodrugs (4/42). Formation of nanoparticles with higher drug loadings was also demonstrated with a hit for an octyl carbamate/carbonate FTC prodrug SDN achieved at 70 wt%. Assessments of in vitro prodrug release from SDNs monitoring FTC formation over time suggested that prodrug release is rate‐limiting under conditions of high SDN concentration. Taken together, this work suggests that carbamate‐based prodrug approaches offer a promising starting point for development of LAI FTC toward a complete LAI‐ARV regimen to improve adherence. Support or Funding Information NIH 1F31AI129549 NIH 5R01AI114405 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .