Effects of intestinal permeation enhancers on solubilization and epithelial transport of the proteolysis targeting chimera (PROTAC) ARV-471 in rats

The molecular properties of proteolysis targeting chimeras (PROTACs) often fall outside the ‘drug-like’ rule of five (Ro5) chemical space, associated with poor intestinal solubility, permeability, and absorption. While formulation strategies have primarily focused on solubility enhancement, the intrinsic permeability barriers of PROTACs and the use of permeation enhancers to modulate them remain largely unexplored. This in vivo rat study assessed the potential of permeation enhancers to improve the intestinal absorption of ARV-471, a model PROTAC characterized by low solubility and permeability (BCS class IV). Intestinal absorption was determined based on plasma drug exposure (AUC 0-4h ) following intraduodenal administration of an amorphous nanosuspension of ARV-471 (2.5 mg/kg), either alone or co-administered with three structurally diverse permeation enhancers (22 mg/kg): salcaprozate sodium (SNAC), lauroyl- l -carnitine (LLC), and sodium caprate (C10). The direct impact of these enhancers (4.4 mg/mL) on effective intestinal permeability was quantified using single-pass intestinal perfusion. These in vivo experiments were complemented by in vitro characterization of the colloidal properties and solubilization potential of ARV-471 in formulations with and without permeation enhancers. This integrated approach allowed the effects of epithelial permeation enhancement to be deconvoluted from those driven by luminal solubilization and dissolution. SNAC increased plasma AUC 0-4h 1.7-fold and enhanced permeability 2.5-fold, with negligible effects on drug solubilization. In contrast, LLC exhibited a dual mechanism, increasing AUC 0-4h 2.5-fold and permeability 2.2-fold, while simultaneously boosting apparent solubility 19-fold. C10 demonstrated only modest effects on absorption, likely related to membrane perturbation. Collectively, these findings demonstrate that permeation-enhancing excipients may improve the oral bioavailability of PROTACs and other BCS Class IV compounds by enhancing luminal solubilization and/or epithelial permeability.