Antiretroviral (ARV) Properties Dictate Long-Acting Release and Tissue Partitioning Behaviors in Multidrug Subcutaneous Implants.

Abstract

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