Bavdegalutamide (ARV-110) Formulations Target Androgen Receptor Degradation via Orodispersible Solid Dispersions
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The androgen receptor (AR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily. In prostate adenocarcinoma, persistent AR signaling remains a primary driver of disease progression, even under aggressive androgen deprivation therapy. Heterobifunctional targeted protein degradation agents, designated as proteolysis targeting chimeras (PROTACs), present a pharmacological strategy distinct from conventional occupancy-based antagonists. Bavdegalutamide (ARV-110) selectively binds the androgen receptor ligand-binding domain while simultaneously recruiting an E3 ubiquitin ligase substrate receptor. This induced proximity triggers polyubiquitination of the receptor, marking it for catalytic destruction by the 26S proteasome. By catalytic turnover of the target protein rather than simple competitive inhibition, this platform achieves sustained suppression of AR-driven genomic programs.
Despite clear biological rationale, clinical development of high-molecular-weight PROTAC chimeras is frequently hampered by poor biopharmaceutical properties. Crystalline drug raw material exhibits severe aqueous insolubility, high lipophilicity, and low dissolution kinetics in gastrointestinal fluids. These characteristics severely restrict oral bio-absorption and lower therapeutic reproducibility in vivo. To overcome these physical barriers, converting the crystalline drug payload into an amorphous solid dispersion (ASD) disrupts the rigid crystal lattice. This solid-state alteration lowers the thermodynamic energy barrier required for drug dissolution into aqueous physiological media.
Orodispersible films (ODFs) represent a versatile oral drug delivery platform designed to accelerate drug dispersion and improve patient compliance. Polyvinyl alcohol (PVA) serves as a suitable hydrophilic matrix-forming polymer due to its high tensile strength and rapid water solubility. Prior to full extrusion trials, vacuum compression molding (VCM) was deployed as a predictive thermal screening tool to evaluate polymer-drug miscibility and degradation thresholds. Formulation viability was subsequently evaluated across two primary manufacturing methods: hot melt extrusion (HME) and solvent casting.
Hot melt extrusion transforms physical drug-polymer blends into homogeneous solid molecular dispersions through mechanical shear and controlled thermal energy. However, processing viscous polymer melts risks thermal degradation of the active pharmaceutical ingredient. To optimize melt rheology, triacetin was incorporated as a low-molecular-weight plasticizer. The addition of triacetin decreased the glass transition temperature (Tg) of the PVA matrix, enabling lower extrusion processing temperatures while preserving chemical integrity. Flow cytometric target engagement assays confirm target engagement dynamics following formulation processing.
Solid-state characterization via differential scanning calorimetry and X-ray powder diffraction verified the complete amorphization of the drug substance within both HME and solvent-casted matrices. While physical mixtures of raw crystalline drug and polymer showed minimal dissolution enhancement, amorphous solid dispersions embedded within solvent-casted ODFs exhibited rapid film disintegration in less than 35 seconds. Rapid hydration of the hydrophilic PVA polymer network enabled swift release of the active compound, maintaining a sustained supersaturated concentration profile without immediate drug precipitation. Consequently, this engineering strategy provides a robust oral delivery system for hydrophobic PROTAC therapeutics such as Bavdegalutamide.
Physicochemical Transformation and Oral Dissolution Optimization
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Bavdegalutamide (ARV-110) operates as a proteolysis targeting chimera (PROTAC) that recruits an E3 ubiquitin ligase to the Androgen Receptor (AR), inducing polyubiquitination and 26S proteasomal degradation. Formulating this hydrophobic payload into polyvinyl alcohol-based orodispersible films as an amorphous solid dispersion circumvents poor aqueous solubility, enabling rapid disintegration and elevated drug dissolution.
Thermal Processing Converts Crystalline Payload to Amorphous Dispersion
Vacuum compression molding established preliminary thermal processing parameters for polymer-drug combinations. Crystalline drug substance underwent complete structural transformation into an amorphous solid dispersion within the polyvinyl alcohol matrix. Differential scanning calorimetry confirmed the loss of crystalline melting endotherms. Triacetin functioned as an effective plasticizing agent. Melt viscosity decreased significantly at lower extrusion temperatures, preventing thermal decomposition of the active molecule. Physical mixtures retained crystalline domains that limited dissolution rates. Solid-state stability was preserved under accelerated stress conditions.
Solvent-Casted Films Demonstrate Rapid Disintegration Under Thirty-Five Seconds
Solvent casting generated homogeneous polymeric films with high structural flexibility. Film disintegration occurred in under thirty-five seconds in aqueous media. Polyvinyl alcohol matrices established rapid hydration channels upon fluid contact. Dissolution rates increased substantially relative to crystalline raw material. Triacetin integration enhanced molecular mobility within the polymeric framework. Cumulative drug release reached high kinetic thresholds within fifteen minutes. Formulated Bavdegalutamide maintained supersaturation without immediate phase separation. These empirical metrics confirm the utility of film matrices for oral PROTAC delivery.