IV-EVE: EVE for Injection-ADME, Pharmacokinetic and Toxicological Evaluation for Novel Deciparticle EVE Formulation

Background: Oral everolimus (Oral-EVE; EVE, Afinitor^®) is an effective therapy for multiple malignancies, including HR-positive/HER2-negative breast cancer, but its clinical use is limited by low and variable oral bioavailability as well as extensive first-pass metabolism. IV-EVE is a Deciparticle™ intravenous formulation of everolimus developed to bypass gastrointestinal absorption and improve systemic pharmacokinetic (PK) predictability. Methods: In vitro ADME properties were assessed across multiple species. IV-EVE (Intravenous EVE, Sapu003) and EVE demonstrated comparable plasma protein binding, metabolic stability, and CYP-mediated metabolism. Pharmacokinetics, tissue distribution, metabolism, and excretion of IV-EVE were evaluated following intravenous administration in rats, with Oral-EVE as a comparator. Results: Elimination of intact everolimus was minimal following either route of administration and occurred predominantly through metabolic biliary/fecal pathways. Compared with Oral-EVE, IV-EVE produced substantially higher and more consistent systemic exposure while maintaining comparable elimination half-lives. Intravenous administration resulted in broad tissue distribution without the marked gastrointestinal accumulation observed following oral dosing. Repeat-dose toxicology studies in rats demonstrated no treatment-related gastric pathology following intravenous administration. Conclusions: These findings suggest that intravenous administration may overcome limitations associated with oral delivery and support the clinical evaluation of IV-EVE in patients with advanced malignancies.