比伐卢定在中国健康受试者中的群体药代动力学和药效学研究

Population pharmacokinetics and pharmacodynamics study of bivalirudin in healthy Chinese subjects

目的建立中国健康受试者静脉注射比伐卢定的群体药代动力学和药效学模型。方法将20例中国男性健康受试者随机分为2组,分别静脉弹丸式给药0. 75 mg·kg^(-1)或静脉弹丸式给药0. 75 mg·kg^(-1)后1. 75 mg·kg^(-1)·h^(-1)静脉滴注1 h。用高效液相色谱串联质谱测定给药前后血浆中比伐卢定的浓度,用非线性混合效应模型(NONMEM)建立群体药代动力学和药效学模型。结果血浆中比伐卢定血药浓度时间曲线符合二室模型,清除率、中央室和外周室的分布容积的群体典型值分别为0. 186 L·min^(-1),3. 17 L和1. 99 L。比伐卢定血药浓度与活化凝血时间(ACT)之间直接相关,符合Sigmoid E_(max)模型,给药后ACT延长值与基线值的比值的最大值(E_(max))、50%的E_(max)时的血药浓度(EC_(50))、Sigmoid系数(曲线陡度,γ)模型估计值分别为269%,5040μg·L^(-1)和0. 824。结论本研究的比伐卢定群体药代动力学和药效学模型稳定、可靠。

Objective To characterize bivalirudin population pharmacokinetics and the correlation between bivalirudin plasma concentration and the activated clotting time(ACT)in Chinese subjects.Methods Twenty healthy male Chinese subjects were enrolled and randomly assigned to two groups,received a bolus intravenous(IV)dose of 0.75 mg·kg-1 biva-lirudin,and the same bolus IV dose of 0.75 mg·kg-1 followed by a one hour IV infusion of 1.75 mg·kg-1·h-1 of bivalirudin,respectively.Population pharmacokinetic(POPPK)and pharmacodynamic(PD)modeling were performed using nonlinear mixed effects modeling(NONMEM).Results Plasma bivalirudin concentration-time profiles in both groups were best described by a two-compartment PK model,and the model estimated systemic plasma clearance(CL),volume of distribution in the central(V1)and peripheral compartments(V2)were0.186 L·min-1,3.17 L and 1.99 L,respectively.The relationship between bivalirudin plasma concentration and ACT was best characterized by a sigmoid Emax model.Model estimated maximum increase of ACT(Emax),the plasma concentration associated with 50%of Emax(EC50),and the sigmoidicity factor(γ,steepness of the curve)were 269%,5040μg·L-1 and 0.824,respectively.Conclusion There was a strong direct correlation between the plasma bivalirudin concentrations and the ACT prolongation.The POPPK and PK/PD models developed in the present study could provide very useful information for dose optimization and individualization in Chinese patients.