Abstract PS4-06-05: Sapu003: Everolimus for Injection — Pharmacokinetic Rationale for Phase I Evaluation in HR+/HER2- Metastatic Breast Cancer

Abstract Background Oral everolimus (Afinitor) is an established therapy for hormone receptor-positive, HER2-negative breast cancer. However, its clinical utility is limited by low and variable oral bioavailability (∼15%), gastrointestinal toxicity, and a narrow therapeutic window driven by first-pass gut extraction and CYP3A/P-gp interactions. Sapu003 is an intravenous Deciparticles™ formulation of everolimus designed to circumvent intestinal loss and toxicity while delivering consistent systemic exposure. Methods Pharmacokinetics (PK), tissue distribution, metabolism, and excretion of Sapu003 were characterized after a single 3 mg/kg IV bolus in Sprague-Dawley rats and a 0.6 mg/kg 30-minute IV infusion in beagle dogs, with oral everolimus (1-3 mg/kg) used as a comparator. Whole blood, organs, feces, and urine were quantified for everolimus by a validated LC-MS/MS method. In vitro plasma, microsome, and hepatocyte stability were assessed across multiple species, including mouse, rat, dog, monkey, and human. Results In rats, IV Sapu003 achieved a mean Cmax of 133 ng/mL and an AUC0-∞ of 339 h·ng/mL, compared with 2.4 ng/mL and 52 h·ng/mL after a 3 mg/kg oral PEG-400 everolimus suspension (representing 55- and 6.5-fold increases, respectively). In dogs, the IV infusion yielded a Cmax of 51-76 ng/mL and an AUC0-∞ of 203-395 h·ng/mL, compared with 8.4 ng/mL and 94-123 h·ng/mL after 1 mg/kg oral Afinitor (representing 6-9- and 2-4-fold increases, respectively), while maintaining comparable half-lives. Plasma, microsome, and hepatocyte stabilities were unchanged relative to everolimus. Sapu003 rapidly distributed to high-flow organs but, unlike oral everolimus, showed low deposition in the gastrointestinal tract. Elimination remained primarily biliary/fecal (>94% of the dose, completed within ≤48 h), with renal clearance accounting for