Development and Validation of an UPLC‐QqQ MS/MS Method for the Determination of Daraxonrasib, a New pan‐KRAS Inhibitor, in Dog Plasma and Whole Blood and Its Application to Pharmacokinetic Studies

Daraxonrasib, an orally administered pan-RAS inhibitor, is undergoing clinical evaluation for pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Defining its pharmacokinetic profile is therefore critical for ongoing progress. Accordingly, a simple and sensitive UPLC-QqQ-MS/MS assay was developed and validated to quantify daraxonrasib in canine plasma and whole blood. Proteins were precipitated with a 20:80 (v/v) acetonitrile-methanol solution containing 0.1% formic acid. Chromatographic separation was performed on a Waters ACQUITY BEH C18 column (50 mm × 2.1 mm, 1.7 μm). The mobile phase consisted of 2 mM ammonium acetate and acetonitrile, each containing 0.1% formic acid, delivered at 0.4 mL/min. Multiple reaction monitoring transitions for daraxonrasib and the internal standard were m/z 811.5 → 680.3 and m/z 724.4 → 396.2, respectively. Calibration standards showed linear response from 1.0 to 1000 ng/mL (r > 0.998). The assay met validation criteria for specificity, recovery, limit of quantification, accuracy, and precision. Finally, this validated method was applied to a dog pharmacokinetic study of daraxonrasib. This report outlines the drug's pharmacokinetic characteristics and supports its continued development.