期刊
出版社
ELSEVIER
DOI: 10.1016/j.jchromb.2021.122806
关键词
Infigratinib; LC-MS; MS; Metabolic stability assessment; In vitro half-life
资金
- Deanship of Scientific Research at King Saud University [RG-1436-024]
Infigratinib (INF) is a novel small molecule inhibitor of human FGFRs, approved by the FDA for the treatment of cholangiocarcinoma. A validated LC-MS/MS method was developed to estimate the concentration of INF in the HLM matrix in this study.
Infigratinib (INF) is a novel small molecule, administered orally, which acts as a human fibroblast growth factor receptors (FGFRs) inhibitor. FGFRs are a family of receptor tyrosine kinases (RTK) reported to be upregulated in various tumor cell types. In 1 December 2020, BridgeBio Pharma Inc. announced FDA approval of INF as a New Drug Application, granting it Priority Review for the treatment of cholangiocarcinoma (CCA). Thus, the current study aimed to establish a validated LC-MS/MS method to estimate the INF concentration in the HLM matrix. In silico prediction of INF metabolism was done using the StarDrop (R) WhichP450TM module to verify its metabolic stability. An accurate and efficient LC-MS/MS analytical method was developed for INF metabolic stability evaluation. INF and duvelisib (DVB) (internal standard; IS) were eluted using an isocratic mobile phase with a C18 column as a stationary reversed phase. The established LC-MS/MS method showed a linear range over 5-500 ng/mL (r2 >= 0.9998) in human liver microsomes (HLMs). The sensitivity of the method was confirmed at its limit of quantification (4.71 ng/mL), and reproducibility was indicated by inter- and intra-day accuracy and precision (within 7.3%). The evaluation of INF metabolic stability was assessed, which reflected an intrinsic clearance of 23.6 mu L/min/mg and in vitro half-life of 29.4 min. The developed approach in the current study is the first LCMS/MS method for INF metabolic stability assessment. Application of the developed method in HLM in vitro studies suggests that INF has a moderate extraction ratio, indicating relatively good predicted oral bioavailability.
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