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

ABSTRACT

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.