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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 pharmacokinetics and pharmacodynamics of domestic bivalirudin for injection in Chinese healthy subjects. Methods: Forty-eight healthy subjects were randomly assigned to receive a single bolus of 0.5, 0.75, 1.05, 0.75 mg.kg-1 intravenous bolus followed by 1.75 mg.kg-1.h-1 4 h (sequential administration). Blood samples were taken at different time points before and after administration to determine the plasma concentrations of bivalirudin, ACT, PA, PT, APTT, And fibrinogen (FIB). The concentration of bivalirudin in the plasma samples of the subjects was determined by HPLC-MS-MS. ACT, PA, PT, APTT, and FIB are clinically tested. RESULTS: (1) Bivalirudin for injection showed a linear pharmacokinetic profile within the dose range of 0.5-1.05 mg.kg-1. There was no accumulation of cisplatin in healthy subjects. (2) After a single intravenous injection of 0.5,0.75,1.05 mg.kg-1 bivalirudin, ACTmax was (149.3 ± 26.4) s, (180.7 ± 21.8) s and (197.3 ± 20.7) s respectively, Regression analysis showed that ACTmax was linearly correlated with dose and Cmax (P <0.05). The peak values of ACT-tmax and plasma concentration peaked at each dose Time tmax, the two paired t test, 0.5 mg.kg-1 and 0.75 mg.kg-1 group no significant difference (P> 0.05); 1.05 mg.kg-1 group was significantly different (P <0.05); Bivalirudin sequential administration at 5 min after administration and 4 h after administration ACT values of ACT-5 min and ACT-4h paired t test showed no significant difference (P> 0.05), indicating that the order The ACT values remained stable within 5 min to 4 h after the beginning of drug administration. The anticoagulant activity of coagulation function (PA, PT, APTT, FIB) showed a linear positive correlation with the dose and plasma concentration. ACT, PA, PT, APTT, FIB returned to normal range after withdrawal. CONCLUSION: Domestic bivalirudin for injection shows anticoagulant activity linearly related to dosage and concentration of ACT by prolonging ACT, APTT, PT time and inhibiting PA. The anticoagulant effect can be immediately induced by intravenous administration. After stopping the coagulation index that is restored to normal range.