A pharmacokinetic study of hematopoietic progenitor kinase 1 inhibitor SYH2040Y in beagles
OBJECTIVE To explore the pharmacokinetic profiles and absolute bioavailability of SYH2040Y,a novel HPK1(hematopoietic progenitor kinase 1)inhibitor,after a single dosing at different doses in beagles.METHODS Beagles were ran-domized into four groups(n=6 each).After a single gavage(0.2/0.5/1.5 mg·kg-1)and intravenous injection(0.2 mg·kg-1),plasma samples were collected at different timepoints and the concentrations determined by validated HPLC-MS/MS and the major pharmacokinetic parameters were calculated by Phoenix WinNonlin 8.3.5 software non-atrial modeling.RESULTS The linear calibration curve of SYH2040Y was obtained over a concentration range of 1-1 000 ng·mL-1.The relative standard devia-tions of inter/intra-batch precision of compound were all less than 8.6％.The inter/intra-batch accuracies ranged from 96.4％to 104.3％.Extraction recovery,matrix effect and stability fulfilled the relevant requirements.The major pharmacokinetic param-eters of SYH2040Y after a single intragastric dose of 0.2/0.5/1.5 mg·kg-1 were AUC0-t(85.39±48.63),(228.19±69.27)and(749.43±171.61)h·ng·mL-1,Cmax(26.93±7.46),(68.16±15.31)and(174.33±65.21)ng·mL-1,tmax(0.92±0.20±7.46),(1.16±0.41)and(1.83±1.17)h and t1/2(2.93±1.49),(2.46±0.85)and(2.20±2.21)h respectively.CONCLUSION The established method is simple,efficient and sensitive.SYH2040Y is rapidly absorbed in beagles after a single dosing with a dose-dependent blood concentration.It has an average absolute bioavailability of 43.9％at all doses.Data supports are provided for conducting and designing of subsequent clinical trials.
small molecule inhibitor of HPK1pharmacokineticsHPLC-MS/MSbeaglesabsolute bioavailability study
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