基于生理药代动力学模型的依达赛珠单抗逆转达比加群的抗凝作用研究  

Study on the reversal of idacelizumab on the anticoagulant effect of dabigatran based on physiological pharmacokinetic model

作　　者：肖珅 张致豪 徐婷婷[2] 项荣武[1,3] 梁露花 XIAO Shen;ZHANG Zhi-hao;XU Ting-ting;XIANG Rong-wu;LIANG Lu-hua(Teaching and Research Section of Biomedical Informatics,Shenyang Pharmaceutical University,Shengyang 110016,Liaoning Province,China;School of Pharmacy,Shenyang Pharmaceutical University,Shengyang 110016,Liaoning Province,China;Medical big data and artificial Intelligence Engineering Technology Research Center of Liaoning,Shengyang 110016,Liaoning Province,China)

机构地区：[1]沈阳药科大学生物医药信息教研室,辽宁沈阳110016 [2]沈阳药科大学药学院,辽宁沈阳110016 [3]辽宁省医药大数据与人工智能工程技术研究中心,辽宁沈阳110016

出　　处：《中国临床药理学杂志》2021年第19期2695-2698,共4页The Chinese Journal of Clinical Pharmacology

基　　金：沈阳药科大学中青年教育事业发展支持计划基金资助项目(ZQN2019016)。

摘　　要：目的通过建立依达赛珠单抗的生理药代动力学(PBPK)模型探讨年龄和肾功能障碍对依达赛珠单抗逆转达比加群抗凝作用的影响。方法查阅相关文献,收集依达赛珠单抗相关的药代动力学(PK)参数和临床试验数据,利用MOBI软件建立其PBPK模型并进行参数优化,并利用误差倍数验证PBPK模型的稳定性。通过PBPK模型预测稀释凝血酶时间(DTT)、静脉酶凝结时间(ECT)和活化部分凝血活酶时间(APTT),将这些参数值与文献值进行比较,确定达比加群的抗凝活性及其相关性。结果依达赛珠单抗的PBPK模型血药浓度和尿液排泄分数预测曲线拟合程度较好,预测模型的PK参数误差倍数均在2倍以内。相同剂量下的中年人和老年人在AUC、初始半衰期和清除率比较差异均无统计学意义(均P>0.05)。DTT、ECT和APTT在中年受试者和老年受试者中平均下降百分比比较差异均无统计学意义(均P>0.05)。肾功能障碍影响了依达赛珠单抗的PK,其中轻度肾功能障碍患者[肌酸酐清除率(Cr Cl)50~<80 mL·min^(-1)]中,依达赛珠单抗的AUC0-24 h和Cmax分别增加了8%和0.8%;中度肾功能障碍患者(Cr Cl 30~<50 mL·min^(-1))增加61%和4%;重度肾功能障碍患者(Cr Cl<30 mL·min^(-1))肾功能障碍患者增加了112%和6%。DTT、ECT和APTT在肾功能状况不同的受试者平均下降百分比比较差异均无统计学意义(均P>0.05)。结论肾功能障碍能够影响依达赛珠单抗和达比加群的PK,年龄和肾功能障碍对于依达赛珠单抗和达比加群酯的抗凝作用的逆转没有影响。Objective To investigate the effects of age and renal dysfunction on idarucizumab ’s reversal of the anticoagulant effect of dabigatran by establishing physiologically based pharmacokinetic(PBPK) model of idarucizumab.Methods The pharmacokinetic(PK)parameters and clinical trial data related to idarucizumab were collected by referring to relevant literatures.The PBPK model was established by MOBI software and the parameters were optimized,and the stability of the PBPK model was verified by the error multiple.PBPK model was used to predict the dilution of thrombin time(DTT),enzyme clotting time(ECT),and the activated partial thromboplastin time(APTT).The values of the parameters were compared with those in the literature to determine the effect of age and renal dysfunction on the anticoagulant activity of dabigatran.Results The PBPK model of idarucizumab showed a good degree of fit for the prediction curves of blood drug concentration and urine excretion fraction;and the error multiple of PK parameters of the prediction model were all within a two-fold range.There was no significant difference in AUC,initial half-life and clearance rate between the middle-aged and the elderly at the same dose(all P>0.05).DTT ECT,and APTT showed no significant difference in the mean percentage reductions of edazumab in middle-aged and elderly subjects(all P>0.05).The PK of edacizumab was affected by renal dysfunction,which the AUC0-24 h and Cmax was increased by 8% and 0.8%,respectively,in patients with mild renal dysfunction [creatinine clearance(CrCl) 50 to 80 mL·min^(-1)];moderate(CrCl 30 to 50 mL·min^(-1)) was increased by 61% and 4%;severe(CrCl <30 mL·min^(-1)) renal dysfunction was increased by 112% and 6%.There was no significant difference in the mean percentage decrease of DTT,ECT and APTT among subjects with different renal function status(all P>0.05).Conclusion Renal dysfunction can affect the PK of idarucizumab and dabigatran.Age and renal dysfunction have no effect on the reversal of Idarucizumab’s anticoagulant

关 键 词：依达赛珠单抗 达比加群 生理药代动力学模型 抗凝作用 肾功能障碍 

分 类 号：R97[医药卫生—药品]