Enabling formulations for PROTACs: A line-of-sight to clinic

Proteolysis targeting chimeras (PROTACs) occupy a challenging oral developability space defined by high molecular weight, elevated polarity and lipophilicity, and substantial conformational flexibility, placing many candidates beyond conventional oral drug-likeness criteria and frequently within Biopharmaceutics Classification System (BCS) class II or IV. These properties create modality-specific constraints in solid-state behaviour, solubility and supersaturation, permeability, and intestinal transport, which together can limit oral absorption and contribute to variable systemic exposure. Many PROTACs exhibit low aqueous and biorelevant solubility, inconsistent maintenance of supersaturation, and uncertain effective permeability complicated by non-specific binding, efflux, and assay-related artefacts, thereby hindering early developability assessment and physiologically based biopharmaceutics modelling (PBBM). To support phase-appropriate development, we propose an early, flexible quality target product profile (eQTPP) framework to guide formulation selection, define evidence requirements for progression, and inform clinical bridging strategy. Within this context, the review evaluates clinically deployable enabling formulation strategies. Solubilisation approaches based on co-solvents, surfactants, and cyclodextrins can increase dissolved concentrations, although their utility is often limited by precipitation on dilution and poor translation to oral solid dosage forms. Lipid-based formulations, including self-emulsifying and supersaturated systems, align with the high lipophilicity of many PROTACs and can improve solubilisation and, in selected cases, permeability or lymphatic access, but may introduce challenges in drug loading, capsule compatibility, and fill stability. Amorphous solid dispersions offer a versatile approach to enhancing dissolution and sustaining supersaturation with favourable manufacturability potential, although polymer-bile interactions and species-dependent effects can generate in vitro-in vivo disconnects. Permeation enhancement remains a secondary strategy constrained by safety, dose, and formulation complexity. The review then considers clinical translation, including fed/fasted state, acid-reducing agent effects, and PBBM-informed bridging, before briefly highlighting future opportunities for local delivery. We therefore propose pragmatic decision frameworks integrating physicochemical characterisation, biorelevant testing, and PBBM to support formulation selection and translation. Overall, successful oral PROTAC development depends on selecting the simplest phase-appropriate enabling strategy that addresses the dominant absorption bottleneck while minimising development risk.