Preconditioning of Long-Acting Subcutaneous Implants to Support Evaluation of In Vivo Pharmacokinetic Depletion Profiles

The pharmacokinetic depletion period (i.e., tail) of long-acting (LA) drug delivery systems can result in a gradual decrease of drug concentration over time. Comprehensive characterization of the depletion tail can provide insight about effectiveness of the drug delivery system and the possibility for subtherapeutic drug levels, which can lower efficacy or enable the emergence of drug-resistant strains. The thorough evaluation of the depletion tail also provides details about the optimal dosing period to maintain therapeutic drug levels throughout the course of treatment. In this study, we explore the preconditioning of a biodegradable subcutaneous implant for LA HIV pre-exposure prophylaxis (HIV PrEP) that sustainably releases antiretroviral (ARV) drug. By preconditioning the implant via accelerated conditions during the zero-order release phase, we can achieve an efficient way of testing long-acting drug formulations.<br/>Poly-ε-caprolactone (PCL) extruded tubes were filled with bictagravir (BIC) formulated with castor oil. The ends of the tubes were heat-sealed and implants were sterilized by gamma irradiation (18-24 KGy). For in vitro release studies, implants were submerged in phosphate-buffered saline (pH 7.4) and drug release was monitored using UV-vis while maintaining sink conditions. Implants were divided into six groups that explored various experimental conditions, including drying, sterilization, and different temperature profiles. Groups 1-4 were used to test in-vitro preconditioning and second round of sterilization and were placed at 37°C for 46 days. After 46 days, Group 1 was placed in an oven at 40°C for two weeks to ensure drying followed by sterilization by gamma irradiation. Group 2 also underwent a drying process but was not sterilized a second time. Group 3 did not undergo a drying process but was sterilized a second time. Group 4 served as the control, which remained in-vitro at 37 °C throughout the duration of the study. To study accelerated conditions, Group 5 was placed at 45°C throughout the study’s duration, and Group 6 was placed at 45°C for 66 days before taken to 37°C for the rest of the study.<br/>The in vitro pre-conditioning of implants resulted in similar release rates of BIC before and after exposure to a second round of sterilization. Also, no notable differences were observed in the release rates of BIC between implants under different experimental conditions for drying or sterilization. For implants exposed to accelerated conditions at 45°C, the release rate increased by 3.2-fold when compared to the control maintained at 37°C. In addition, devices switched from 45°C to 37°C demonstrated release rates similar to the control group, showing that release rates can be tuned through temperature change.<br/>In this work, we demonstrate an advantageous method to precondition long-acting subcutaneous implants to support subsequent in vivo studies. Our results show that implants are unaffected after removal from in-vitro conditions and after a drying process and a second round of sterilization. In addition, we demonstrate a successful acceleration of in vitro drug release using a higher temperature (45°C). This approach can potentially shorten the timeframe of preclinical studies by preconditioning implantable drug delivery systems during the phase of zero-order release kinetics. Overall, this approach supports approaches to characterize LA drug delivery systems without sole reliance on long-term animal studies.