Abstract 1858: Nanoformulation strategy for oral delivery of KRAS inhibitor (sotorasib): pH-independent dissolution to mitigate PPI drug interaction

Abstract Biovariability poses a significant challenge in the oral administration of sotorasib (AMG 510), an FDA-approved KRAS G12C inhibitor for non-small cell lung cancer (NSCLC). Sotorasib, a weakly basic drug with limited aqueous and pH-dependent solubility, necessitates a high daily dose (960 mg; 8 tablets). In general, high doses, pill burdens, and poor solubility often result in poor patient compliance and therapeutic outcomes. Co-administration with proton pump inhibitors (PPIs) in cancer patients significantly reduces the bioavailability of weakly basic drugs including sotorasib. To address these limitations, we developed a pH-independent nanocrystalline formulation through wet media milling, aiming to achieve a stable formulation with enhanced bioavailability, improved redispersibility, and minimized fasted/fed variability. The nanosuspension, formulated using anionic surfactant and non-ionic polymer as stabilizers, achieved a high drug load (45% w/w) with uniformly distributed nanocrystals (173 ± 21.54 nm) and a negative zeta potential (-36.0 ± 0.57 mV). Cryoprotectants hydroxypropyl-β-cyclodextrin (HPβ-CD) and trehalose were effective in preventing aggregation, ensuring excellent redispersibility across pH conditions in both simulated gastric (pH 4.0) and intestinal (pH 6.8) environments. In vitro dissolution studies demonstrated > 95% drug release within 5 minutes at both pH levels, indicating rapid dissolution and robust stability. Solid State Characterization studies, including X-ray diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and cryo-TEM, confirmed the preserved crystallinity, reduced particle size, and improved homogeneity. Additionally, BET surface area analysis indicated an increased surface area for the lyophilized nanosuspension, supporting enhanced dissolution. The in-silico model predicted increased absorption in the intestinal region, particularly the duodenum and jejunum due to improved saturation solubility and minimized drug precipitation. In vivo pharmacokinetic studies in SD rats revealed superior systemic exposure, with a significant increase in Cmax (3529 ± 564.57 ng/mL) and AUClast (8294.5 ± 1346.66 h*ng/mL) compared to the physical mixture. It may address the challenges of high dosing requirements and drug interactions with acid-reducing agents, offering a promising solution to enhance therapeutic outcomes for lung cancer patients. Citation Format: Henis Patel, Akanksha Patel, Ketan Patel. Nanoformulation strategy for oral delivery of KRAS inhibitor (sotorasib): pH-independent dissolution to mitigate PPI drug interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1858.