国产比伐卢定在10名健康男性受试者体内的初步药动-药效学研究及安全性评价  

Preliminary pharmacokinetic and pharmacodynamic studies and safety evaluation of homemade bivalirudin in 10 healthy male subjects

作　　者：杨克旭[1] 林阳[1] 刘文芳[1] 李静[1] 所伟[1] 吴伟[1] 仇琪[1] 杜海燕[1] 周子杰[1] 赵桂平[1] 王云龙[1] 潘昱[1] 闫秀娟[1] 贾小欣[1] 

机构地区：[1]首都医科大学附属北京安贞医院药物临床试验机构,100029

出　　处：《药物不良反应杂志》2012年第5期282-285,共4页Adverse Drug Reactions Journal

摘　　要：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 pharmacokinetic and pharmacodynamic characteristics of homemade bivalirudin in healthy male subjects and evaluate its safety preliminarily in order to provide the scientific basis for a phase Ⅱ/Ⅲ clinical trial and clinical use of the drug. Methods Healthy male subjects were collected and received a single intravenous bolus injection of bivafirudin 0.75 mg/kg. Plasma concentrations of bivalirudin within 180 min after injection were determined by liquid chromatography-tandem mass spectrometric （LC-MS/MS） method for phal3nacokinetic analysis. The activated clotting time were measured for pharmacodynamic analysis. At the same time, the vital signs and safety evaluation indexes were observed in all subjects before and after medication. Results Ten healthy male subjects were entered. Their age, height, weight, and body mass index were （29.5 ± 3.4） years, （ 170. 7 ± 5.5 ） cm, （66 ± 7） kg, and （22.2 ± 1.7） kg/m2, respectively. The pharmacokinetic parameters were as follows ： peak concentration （Cmax） （8347 ± 1586） μg/L, peak time （Tmax ） 5 min, elimination half-life （Tl/2z）（41.6± 9.0） min, area under the curve（ A UC0-1 ） 124. 0 （ 98.4-182.3 ） min · μg/L, area under the curve （ A UC0-∞ ） （ 131.9 ± 26.8 ） rain · μg/L, mean retention time （MRT0-1 ） （25.6 ± 3.1 ） rain, volume of distribution （ Vz） （ 354.8 ± 103.9 ） ml/kg, clearanee （CL） （5.9 ± 1.1 ） ml/（ min · kg）. The pharmaeodynamic parameters were as follows ： basic effect （ E0 ） （ 146 ± 17 ） s, concentration for 50% of maximal effect （ ECso ） 2225 （799-42 008 ） μg/L, maximal effect （Emax） （4072 ± 294 ） s. No ehanges in X-ray, cranial CT, 12-lead ECG and laboratory examination （routine blood and urine tests, blood biochemical tests, immunologieal tests, 5 tests of coagulation） were observed after the trail. No adverse drug reaction oceurred during the trial. Conclusion Homemade bivalirudin seems to have the charac

关 键 词：比伐卢定 药动学 药效学 活化凝血时间 

分 类 号：R96[医药卫生—药理学]