小分子抑制剂SYH2040Y的比格犬药动学研究  

A pharmacokinetic study of hematopoietic progenitor kinase 1 inhibitor SYH2040Y in beagles

作　　者：康凯 王小彦 刘晓琳 吴艳波 杨汉煜[2] KANG Kai;WANG Xiaoyan;LIU Xiaolin;WU Yanbo;YANG Hanyu(School of Pharmacy,Hebei Medical University,Hebei Shijiazhuang 050011;CSPC Zhongqi Pharmaceutical Technology Inc(Shijiazhuang),Hebei Shijiazhuang 050035,China)

机构地区：[1]河北医科大学药学院,河北石家庄050011 [2]石药集团中奇制药技术(石家庄)有限公司,河北石家庄050035

出　　处：《中国医院药学杂志》2024年第13期1508-1512,1547,共6页Chinese Journal of Hospital Pharmacy

基　　金：河北省科技研发平台建设专项(编号:199676133H)。

摘　　要：目的:研究新型HPK1(造血祖细胞激酶1)抑制剂SYH2040Y在比格犬体内不同剂量下单次给药后的药动学特征和绝对生物利用度。方法:将比格犬随机分为4组,每组6只,雌雄各半,经单次灌胃(0.2、0.5、1.5 mg·kg^(-1))和静脉注射(0.2 mg·kg^(-1))给药后,分别在不同时间点收集血浆样品,采用经验证的HPLC-MS/MS方法测定其浓度,并使用Phoenix WinNonlin 8.3.5软件非房室模型计算主要的药动学参数。结果:该方法的线性范围为1.00~1000 ng·mL^(-1),批内和批间精密度试验的RSD均小于8.6%,批内和批间准确度在96.4%~104.3%,提取回收率、基质效应和稳定性均满足相关要求。犬体内试验结果显示,比格犬灌胃给予低、中、高3个剂量后,血浆中SYH2040Y的AUC0-t分别为(85.39±48.63)、(228.19±69.27)、(749.43±171.61)h·ng·mL^(-1),Cmax分别为(26.93±7.46)、(68.16±15.31)、(174.33±65.21)ng·mL^(-1),t_(max)分别(0.92±0.20)、(1.16±0.41)、(1.83±1.17)h,t_(1/2)分別为(2.93±1.49)、(2.46±0.85)、(2.20±2.21)h。结论:建立的方法简单、高效、灵敏,经测定单次给药后,SYH2040Y在比格犬体内吸收迅速,血药浓度呈现剂量依赖性,在各剂量下,其平均绝对生物利用度为43.9%,可为后续临床试验的推进及设计提供数据支持。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 randomized 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 1-1000 ng·mL^(-1).The relative standard deviations 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 parameters 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.

关 键 词：HPK1小分子抑制剂 药动学 液相色谱-串联质谱法 比格犬 绝对生物利用度 

分 类 号：R969.1[医药卫生—药理学]