比伐卢定在健康人体内的药动学和药效学  

Pharmacokentics and pharmacodynamics of intravenous bivalivudin for injection in health Chinese volunteers:a randomized,open-label,single-and multiple-dose study

作　　者：张梅[1] 徐琳[1] 邸晓辉[1] 徐娟[1] 许红霞[1] 田新莉[2] 王金萍[1] 陈艳[1] 

机构地区：[1]中国人民解放军北京军区总医院药理科,北京100700 [2]中国人民解放军北京军区总医院心肺血管病中心,北京100700

出　　处：《中国医院药学杂志》2012年第16期1260-1264,共5页Chinese Journal of Hospital Pharmacy

摘　　要：目的:研究国产注射用比伐卢定在中国健康受试者体内药动学、药效学特点。方法:将48名健康受试者随机分组,分别接受单次静脉推注0.5,0.75,1.05,0.75 mg.kg-1静脉推注后续以1.75 mg.kg-1.h-1匀速静脉滴注4 h(序贯给药)。给药前后不同时间点取血测定比伐卢定的血药浓度、活化凝血时间(ACT)、凝血酶原活动度(PA)、凝血酶原时间(PT)、部分凝血酶原时间(APTT)和纤维蛋白原(FIB)。采用HPLC-MS-MS法测定受试者血浆样品中比伐卢定的浓度。ACT、PA、PT、APTT和FIB为临床检验所得。结果:(1)注射用比伐卢定在0.5～1.05 mg.kg-1的剂量范围内,呈线性药动学特征;序贯给药在健康受试者体内不存在蓄积。(2)单次静脉推注0.5,0.75,1.05 mg.kg-1比伐卢定后,ACTmax分别为(149.3±26.4)s、(180.7±21.8)s和(197.3±20.7)s,与给药剂量和Cmax进行回归分析,并对回归系数t检验,表明ACTmax与给药剂量和Cmax呈线性相关特征(P<0.05);各剂量组药效达峰时间ACT-tmax与血药浓度达峰时间tmax,二者配对t检验,0.5 mg.kg-1和0.75mg.kg-1组差异无显著性(P>0.05);1.05 mg.kg-1组差异有显著性(P<0.05);比伐卢定序贯给药在给药后5 min和给药后4 h ACT值即ACT-5 min和ACT-4h进行配对t检验,结果显示差异无显著性(P>0.05),说明序贯给药开始5 min至4 h范围内,ACT值维持稳定。凝血功能(PA、PT、APTT、FIB)指标显示的抗凝血活性与给药剂量和血药浓度呈线性正相关。停药后ACT、PA、PT、APTT、FIB恢复至正常值范围。结论:国产注射用比伐卢定通过延长ACT、APTT、PT时间,同时抑制PA,呈现出与用药剂量和浓度线性相关的抗凝血活性,且静脉给药可立即产生抗凝血作用。停药后各项凝血指标即恢复至正常范围。OBJECTIVE To study the pharmacokinetic and pharmacodynamic characteristics of domestic bivalrudin for injection in Chinese health volunteers.METHODS Forty-eight health volunteers were randomized to receive a bivalirudin 0.5,0.75,1.05 mg·kg-1 by single intravenous injection and a bivalirudin 0.75 mg·kg-1 single intravenous injection followed by a 4-hour infusion at 1.75 mg·kg-1·h-1.At a series of time points before or after administration,the blood samples ware collected for plasma drug level,activated clotting time（ACT）,prothrombin activity（PA）,prothrombin time（PT）,activated partial thromboplastin time（APTT）,fibrinogen（FIB）.Drug level were determinde by LC-MS-MS.ACT,PA,PT,APTT and FIB were detemined by clinical laboratory.RESULTS When the dosage of bivalirubin are 0.5-1.05 mg·kg-1,there is linear pharmacokinetic character.Drug accumulation was not detected after sequential administration.When bivalirubin were administered at a bolus dose of 0.5,0.75,1.05 mg·kg-1,ACTmax are respectively（149.3±26.4）s,（180.7±21.8）s and（197.3±20.7）s,and are linear corrected to dosage（P0.05）.The relation between peak time of effect（ACT-tmax） and peak time of drug level（tmax） was analysised.The difference between ACT-tmax and tmax was not significant（P0.05） when the dosage were 0.5 mg·kg-1 and 0.75 mg·kg-1,but it was significant（P0.05） when the dosage were 1.05 mg·kg-1.When the drug was administered by infusion after bolus sequentially,The difference between ACT-5min and ACT-4h was not significant（P0.05）,this indicated that ACT was maintained in stable range when the drug was infused.The levels of PA,PT,APTT and FIB are linear corrected to dosage and plasma drug level and return to normal range soon after drug discontinuance.CONCLUSION Domestic bivalirdin increase the level ACT,APTT and PT,and dicrease the level of PA,the effect of anticoagulation is linear corrected to dosage and plasma drug level.The clinic indexes of blood clotting return to normal range soon after

关 键 词：注射用比伐卢定 药动学 药效学 活化凝血时间 凝血功能 

分 类 号：R969[医药卫生—药理学]