Development and Validation of the Novel, Fast Bioanalytical LC‐MS/MS Technique for the Simultaneous Estimation of Sotorasib and Ondansetron: Application to In Vivo Pharmacokinetic Assessments

ABSTRACT The present study aims to evaluate the in vivo drug interactions between sotorasib and ondansetron to provide critical data for accidental or self‐medication cases to ensure safe and effective concurrent use. A rapid UHPLC‐MS/MS technique was developed on a Zorbax Eclipse XDB‐C18 column (3.0 × 100 mm, 3.5 μm) using ammonium bicarbonate and methanol. The MRM analysis identified distinct transitions for sotorasib, ondansetron, and the internal standard (IS) at m/z 561.2 → 134.0, 317.0; m/z 294.0 → 184.0, 170.0; and m/z 529.2 → 326.1, 160.9, respectively. Target analytes were extracted from rat plasma by organic solvent precipitation. The UHPLC‐MS/MS method revealed linearity as R 2 > 0.99, sensitivity at 0.4 ng/mL concentration, accuracy as 99.15%–99.87%, and precision as 1.62%–6.45% for LQC, MQC, and HQC. In silico predictive assessments revealed moderate and serious risk levels. Preclinical pharmacokinetic study revealed that ondansetron exhibited diminished C max (0.69‐fold), AUC (0.45‐fold), and half‐life (0.75‐fold), alongside increased clearance (2.04‐fold) when administered concurrently. Study findings are likely due to CYP3A4 induction by sotorasib, overriding its P‐gp inhibition effects. To alleviate these effects, physicians must consider dose adjustments or stringent alternative antiemetic strategies.