Pharmacokinetic and safety evaluation of lipopeptide-based HIV fusion inhibitor Lipovirtide in rats

Lipovirtide, originally designated as LP-80, is a stearic acid-modified lipopeptide HIV fusion inhibitor with highly potent and long-lasting anti-HIV activity, and it has already progressed to phase II clinical trials. In this report, we investigated the pharmacokinetics and safety profile of LP-80 in Sprague Dawley (SD) rats. LP-80 was absorbed rapidly following subcutaneous injection, exhibiting high absolute bioavailability (F): 92.32 % in male and 84.74 % in female. The time to reach maximum plasma concentration (T_max) ranged from 5.5 to 8 hours (h), and the elimination half-life (T_1/2) was between 6.26 and 7.47 h, indicating a relatively long-lasting presence in the bloodstream. LP-80 was widely distributed across various tissues, with the highest concentration observed in serum, suggesting effective systemic delivery and potential for targeting HIV in different compartments. Only a minimal amount of the parent drug was excreted in feces and urine, which indicates that LP-80 is metabolically stable and not rapidly cleared from the body. Acute, subchronic, and chronic toxicity studies demonstrated that LP-80 was well tolerated in animals, with no significant adverse effects observed. No anti-drug antibodies (ADA) were detected, suggesting low immunogenicity. Furthermore, LP-80 showed no toxic effects on fertility, embryo-fetal development, or offspring development. Collectively, our studies demonstrate that LP-80 is metabolically stable and exhibits a favorable safety profile, supporting its advancement into clinical trials for HIV treatment.