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目的初步研究国产比伐卢定在健康男性受试者体内的药动学和药效学特点并评价其安全性,为Ⅱ/Ⅲ期临床试验及临床应用提供科学依据。方法收集健康男性受试者,单次静脉弹丸式注射比伐卢定0.75 mg/kg,以液相色谱-串联质谱法测定给药后180 min内的血药浓度进行药动学分析,测定活化凝血时间进行药效学分析,同时观察给药前后受试者生命体征及安全性检查指标的变化。结果入选健康男性受试者10名,年龄(29.5±3.4)岁,身高(170.7±5.5)cm,体重(66±7)kg,体重指数(22.2±1.7)kg/m2。药动学参数:峰浓度(Cmax)为(8347±1586)μg/L,达峰时间(Tmax)为5 min,末端消除半衰期(T1/2z)为(41.6±9.0)min,0到t药时曲线下面积(AUC0-t)为124.0(98.4～182.3)min.μg/L,0到无穷药时曲线下面积(AUC0-∞)为(131.9±26.8)min.μg/L,平均驻留时间(MRT0-t)为(25.6±3.1)min,表观分布容积(Vz)为(354.8±103.9)ml/kg,清除率(CL)为(5.9±1.1)ml/(min.kg)。药效学参数:基础值(E0)为(146±17)s,半最大效应浓度(EC50)为2225(799～42 008)μg/L,最大效应(Emax)为(4072±294)s。试验结束后,所有受试者行X线胸片、头颅CT、12导联心电图及实验室检查(血尿常规、血生化、免疫、凝血5项检查),均未见异常。试验过程中受试者无不良反应发生。结论国产比伐卢定似有起效快和半衰期较短的特点,可作为一种较安全的抗凝剂用于经皮冠状动脉介入治疗的患者。
OBJECTIVE: To study the pharmacokinetics and pharmacodynamics of domestic bivalirudin in healthy male subjects and to evaluate its safety, and to provide a scientific basis for phase Ⅱ / Ⅲ clinical trial and clinical application. Methods Healthy male subjects were enrolled in a single intravenous bolus injection of bivalirudin 0.75 mg / kg. The pharmacokinetics of the drug was determined by liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) Coagulation time for pharmacodynamic analysis, while observing the test subjects before and after treatment of vital signs and safety indicators of change. Results A total of 10 healthy male subjects were enrolled. Their ages (29.5 ± 3.4) years, height (170.7 ± 5.5) cm, body weight (66 ± 7) kg and body mass index (22.2 ± 1.7) kg / m2. The pharmacokinetic parameters were as follows: the peak concentration (Cmax) was (8347 ± 1586) μg / L, the peak time (Tmax) was 5 min, the terminal elimination half-life (T1 / 2z) was (41.6 ± 9.0) The area under the curve (AUC0-t) was 124.0 (98.4-182.3) min.μg / L, and the area under the curve (AUC0-∞) from 0 to the infinite drug was (131.9 ± 26.8) min.μg / The time (MRT0-t) was (25.6 ± 3.1) min, the apparent volume of distribution (Vz) was (354.8 ± 103.9) ml / kg and the clearance rate was (5.9 ± 1.1) ml / (min.kg). The pharmacodynamic parameters were as follows: the basal value (E0) was (146 ± 17) s, the EC50 was 2225 (799 ~ 42008) μg / L and the maximum effect was (4072 ± 294) s. After the test, all the subjects underwent X-ray, CT, 12-lead electrocardiogram and laboratory tests (routine examination of hematuria, blood biochemistry, immunity and coagulation) without any abnormality. Subjects during the test without adverse reactions occurred. Conclusion Domestic bivalirudin has the characteristics of fast onset and short half-life and may be used as a safer anticoagulant in patients undergoing percutaneous coronary intervention.