The In Vivo Effect of Amorphous Drug Nanoprecipitates on the Intestinal Absorption of the PROTACs ARV-110 (Bavdeglutamide) and ARV-471 (Vepdegestrant).

Targeted degradation of disease-associated proteins via proteolysis-targeting chimeras (PROTACs) is a powerful pharmacological strategy, but it requires a complex molecular architecture associated with poor intestinal absorption. Rational development of orally bioavailable PROTACs requires a thorough understanding of their biopharmaceutical properties. This mechanistic in vivo study aimed to address the potential of colloidal particle formulations to enhance the intestinal absorption of two model PROTACs, ARV-110 and ARV-471. Dose escalation studies were conducted in rats to investigate the impact of particle size and concentration on intestinal absorption and bioavailability of the PROTACs. The contribution of colloidal amorphous drug nanoprecipitates was moreover directly quantified by comparing intestinal absorption from a colloid-forming formulation with that of an amorphous, noncolloidal counterpart. All in vivo experiments were complemented by in vitro determinations of amorphous solubility, solubilization dynamics, and characterization of the size and solid state of the emerging colloidal particles. The two PROTACs consistently formed luminally stable, amorphous drug nanoprecipitates in vivo. Dose-proportional increases in absorption were observed at concentrations up to 15-fold above their amorphous solubility. The amorphous drug nanoprecipitates directly contributed to an enhanced absorptive flux up to 7-fold compared to a noncolloidal amorphous powder. The potentiating effect was attributed to particle drifting of the nanoparticles across the aqueous boundary layer, which increased the free drug concentration at the epithelial membrane. For the less soluble ARV-110, the colloid effect was capped at doses >0.2 mg/kg due to saturation. For the more soluble ARV-471, the colloid effect persisted at doses up to 5.0 mg/kg but at a reduced rate due to the formation of larger, less mobile particles. Overall, this work provided mechanistic insight into PROTAC absorption and suggested that formulations capable of generating stable amorphous drug nanoprecipitates represent a promising strategy to enhance the oral bioavailability of low-solubility PROTACs.