Optimizing Preclinical and Clinical Translation: A Multi-Species Computational Model for Islatravir and Etonogestrel Formulation for Improvements in Long-Acting Strategies

The development of effective and safe HIV prevention strategies is essential for addressing the ongoing epidemic. Islatravir (ISL), a novel nucleoside reverse transcriptase translocation inhibitor, shows promise as a long-acting (LA) pre-exposure prophylaxis (PrEP) agent. To reduce reliance on animal experimentation while enhancing translational efficiency, we developed a multi-compartment, multi-species computational pharmacokinetic (PK) model in MATLAB SimBiology. This model simulates ISL plasma levels and active intracellular ISL-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) across humans, non-human primates (NHPs), and rats for four administration routes: oral bolus, intravenous injection, subcutaneous injection, and subcutaneous implant. The model was validated using both published data and experimental results from subcutaneous implant studies, accurately capturing interspecies pharmacokinetic variability. Simulations predicted ISL-triphosphate concentrations needed to achieve preventive efficacy in PBMCs (>0.05 pmol/10⁶ cells for humans and NHPs) while optimizing dosage and release rates. Our findings highlight the potential of computational modeling to refine dose selection, reduce experimental animal use, and accelerate the development of LA-PrEP strategies. This approach facilitates preclinical-to-clinical translation, offering a valuable tool for optimizing ISL delivery systems to maximize HIV risk reduction with minimal adverse effects. This in silico methodology underscores the promise of integrating computational models into the development pipeline for long-acting PrEP strategies, advancing ISL as a safe and effective intervention. Alongside in-silico approach involving ISL, conventional investigational studies both in-vitro and in-vivo were conducted to optimize Etonogestrel (ENG) formulation, a synthetic progestin used primarly for contraception that could give an additional layer of protection to subdermal implants.