Antiretroviral\n(ARV) Properties Dictate Long-Acting\nRelease and Tissue Partitioning Behaviors in Multidrug Subcutaneous\nImplants

Subcutaneous implants can provide\npatients with long-acting,\ncompliance-independent\ndrug dosing. For this reason, subcutaneous implants have shown emerging\ninterest in human immunodeficiency virus (HIV) prevention. However,\nany successful long-acting HIV-prevention device will require multidrug\ndosing, which poses a challenge for formulation considering the physicochemically\ndiverse selection of antiretroviral (ARV) candidates. As a method\nthat has shown the capacity of efficient multidrug delivery, we assessed\nelectrospun fiber implants composed of three synergistically potent\nARVs and a biodegradable polymer selected by <i>in vitro</i> release studies. In mice, subcutaneous electrospun fiber implants\nexhibit burst release of the more hydrophilic drugs maraviroc (MVC)\nand raltegravir (RAL), which could be reduced <i>via</i> simple prewash treatments of the implants. Over an extended 120\nday time frame, fiber implants show drug-specific differences in release\ntime frames and magnitudes in blood serum. However, end-point drug\ntissue concentrations show that the most hydrophobic drug etravirine\n(ETR) remains in high concentrations within the implant and in local\nskin tissue biopsies. Furthermore, ETR is found to be capable of significant\npartitioning into lymph nodes, the lower female reproductive tract,\nand the rectum. Topologically smooth film implants also exhibit the\nsame drug-dependent trends. Therefore, we illustrate that drug release\nand drug tissue partitioning are largely dictated by drug properties.\nFurther, we find that the properties of ETR enable significant drug\nquantities within the tissues most relevant to HIV protection. Evidence\nfrom this work emphasizes the need for a greater focus on drug properties\nand prodrug strategies to enable relevant, extended, and targeted\ndrug release.