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

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 R² > 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.