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.