Ultra‐Fast UPLC‐MS/MS Method for the Ripretinib Quantification in the HLMs Matrix With Metabolic Stability Assessment: In‐Silico Study for Toxic Alerts and the Metabolic Lability

Ripretinib (QINLOCK) is a broad-spectrum, orally-administered, switch-controlled kinase inhibitor that got FDA approval in May 2020 for the treatment of advanced gastrointestinal stromal tumors (GIST) in adult patients who have formerly had treatment with three or more kinase inhibitors, comprising imatinib. This study sought to develop a precise, rapid, dependable, and sustainable UPLC-MS/MS approach for measuring ripretinib (RPB) in the human liver microsomes (HLMs) matrix, utilized for assessing the metabolic stability of RPB. The validation processes for the UPLC-MS/MS system adhered to US-FDA rules for bioanalytical technique validation. The validated method utilized HLMs matrix throughout a level range of 1-4000 ng/mL with a duration of 1 min. The precision (%RSD) and accuracy (%E) rates for intraday and interday measurements varied from -0.6% to 9.3% and -2.5% to 15.3%, respectively. The StarDrop software employed P450 and DEREK modules to evaluate metabolic lability and to characterize RPB structural warnings, respectively. The in-vitro t_1/2 was calculated to be 47.4 min, and the intrinsic clearance (Cl_int) of RPB was computed to be 17.1 mL/min/kg. In-silico assessments indicate that slight structural changes to the methyl amino group (97%) and the phenylurea moiety (3%) in drug design could increase the metabolic stability of RPB. The evaluation of in-silico RPB ADME characteristics and metabolic stability is fundamental for progressing innovative drug research focused on augmenting metabolic stability.