Integrative Analysis of Pharmacokinetic and Metabolomic Profiles for Predicting Metabolic Phenotype and Drug Exposure Caused by Sotorasib in Rats

Sotorasib is a novel targeted inhibitor of Kirsten rat sarcoma (KRAS) (G12C) that has shown exciting tumor-suppressing effects not only for single targeted agents but also for combination with immune checkpoint inhibitors. However, no integrative analysis of the pharmacokinetics (PK) and pharmacometabolomics (PM) of sotorasib has been reported to date. In the present study, a sensitive and robust high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method was firstly developed and fully validated for the quantitation of sotorasib in rat plasma. After one-step protein precipitation, sotorasib and an internal standard (carbamazepine) were separated on a Waters XBrige C(18) column (50 mm × 2.1 mm, 3.5 μm) and analyzed in electrospray ionization positive ion (ESI(+)) mode. The optimized method was fully validated according to guidance and was successfully applied for the PK study of sotorasib at a dose of 10 mg/kg. In addition, a longitudinal and transversal PM was employed and correlated with PK using partial least squares model and Pearson’s analysis. With multivariate statistical analysis, the selected six (AUC model) and nine (C (max) model) metabolites completely distinguished the high- and low-exposure groups after sotorasib treatment, which indicates that these potential biomarkers can predict drug exposure or toxicity. The results of this study will not only shed light on how sotorasib disturbs the metabolic profiles and the relationship between PK and PM but also offer meaningful references for precision therapy in patients with the KRAS (G12C) mutation.