中国药理学与毒理学杂志2021，Vol.35Issue(1)：18-26,9.DOI:10.3867/j.issn.1000-3002.2021.01.003
新型重组活化凝血因子Ⅶa候选药物GEN-0828定量检测方法的建立及其在血友病模型小鼠中的药动学特征
Development of quantification method for GEN-0828, a novel recombinant activated clotting factor Ⅶa candidate drug, and its pharmacokinetic character istics in hemophilia B model mice
摘要
Abstract
OBJECTIVE To develop a sensitive method for the detection of GEN-0828 in plasma from hemophilia model mice and to explore the pharmacokinetic profiles of GEN-0828 in hemophilia mouse models. METHODS A quantification method for GEN-0828 in plasma was established and validated. A bonus of GEN-0828 (90.9 kU · kg-1) was injected into the tail vein of factor Ⅸ (FⅨ) knock?out (B-F9 KO) model mice. Then, the concentration of GEN-0828 in plasma was detected by activated factor Ⅶa (FⅦa) activity assay. The pharmacokinetic parameters were analyzed with WinNonlin 6.4 software for non-compartmental model analysis. RESULTS A good linearity was demonstrated from 62.5 to 2000 U·L-1 for GEN-0828 (R2=0.9988) and the lower limit was 62.5 U·L-1. The intra-day and the inter-day precisions were 3.9％-5.2％ and 5.2％-11.1％, and the accuracy was -3.5％ to 1.8％. The selective relative error (RE) was-15.9％ to 13.8％;the relative standard deviation (RSD) of parallelism was below 4.3％, and there was no dilution effect in the range of 5-40 times dilution of samples. After validation, the method was stable at room temperature for 3 h, at-20℃for 141 d, and at-80℃for 92 d. Moreover, the main pharmacokinetic parameters of GEN-0828 in B-F9 KO model mice were as follows:the terminal elimination half-life (t1/2) was (3.73 ± 0.15) h, the area under the plasma concentration-time curve from zero to the last sampling time (AUClast) was (115 ± 23) h · kU · L-1, the volume of distribution (Vz) was (3.7±0.7) L·kg-1, and the total body clearance (Cl ) was (0.69±0.12) L·h-1·kg-1. CONCLUSION A sensitive and specific quantitative method is established to determine the concentration of GEN-0828 in plasma, and may be applied in preclinical pharmacokinetic studies in hemophilia B model mice, thus facilitating fature research on this novel drug.关键词
重组活化的凝血因子Ⅶ/血友病/药动学Key words
recombinant activated factor Ⅶ/hemophilia/pharmacokinetics分类
医药卫生引用本文复制引用
刘雨璐,朱晓霞,甘慧,吴卓娜,李俭,冯素香,窦桂芳,顾若兰,孟志云..新型重组活化凝血因子Ⅶa候选药物GEN-0828定量检测方法的建立及其在血友病模型小鼠中的药动学特征[J].中国药理学与毒理学杂志,2021,35(1):18-26,9.基金项目
国家科技重大专项(2018ZX09J18111-003)National Science and Techonology Major Project of China(2018ZX09J18111-003) （2018ZX09J18111-003）
