4.4 Article

Development and validation of an HPLC-MS/MS method to quantify the KRAS inhibitor adagrasib in mouse plasma and tissue-related matrices

Journal

BIOMEDICAL CHROMATOGRAPHY
Volume -, Issue -, Pages -

Publisher

WILEY
DOI: 10.1002/bmc.5720

Keywords

adagrasib; bioanalysis; KRAS inhibitor; LC-MS; MS; mouse matrices

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We developed and validated a liquid chromatography-tandem mass spectrometry assay to quantify the KRAS inhibitor adagrasib in mouse plasma and tissue-related matrices. The assay demonstrated a linear calibration range, good precision, and accuracy across various matrices. This method was successfully applied to determine the pharmacokinetic profile and tissue distribution of adagrasib in wild-type mice.
We developed and validated an assay utilizing a liquid chromatography-tandem mass spectrometry technique to quantify the KRAS inhibitor adagrasib in mouse plasma and seven tissue-related matrices. The straightforward protein precipitation technique was selected to extract adagrasib and the internal standard salinomycin from the matrices. Gradient elution of acetonitrile and water modified with 0.5% (v/v) ammonium hydroxide and 0.02% (v/v) acetic acid on a C-18 column at a flow rate of 0.6 ml/min was applied to separate the analytes. Both adagrasib and salinomycin were detected with a triple quadrupole mass spectrometer with positive electrospray ionization in a selected reaction monitoring mode. A linear calibration range of 2-2,000 ng/ml of adagrasib was demonstrated during the validation. In addition, the reported precision values (intra- and inter-day) were between 3.5 and 14.9%, while the accuracy values were 85.5-111.0% for all tested levels in all investigated matrices. Adagrasib in mouse plasma was reported to have good stability at room temperature, while adagrasib in tissue-related matrices was stable on ice for up to 4 h (matrix dependent). Finally, this method was successfully applied to determine the pharmacokinetic profile and tissue distribution of adagrasib in wild-type mice.

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