| Objective To study the pharmacokinetics, pharmacodynamics and safety of bivalirudin in healthy Chinese volunteers, and to develop the Pharmacokinetic-Pharmacodynamic(PK/PD)model of bivalirudin to design suitable dosage regimen of bivalirudin during percutaneous coronary intervention (PCI) operation.Methods①A method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of bivalirudin concentration in plasma was developed, and the methodology was assayed including the specificity,sensitivity, precision, average recovery ratio, stability, dilution effect and matrix effect.②Applying the open, single dose and dose climbing design, 36 healthy Chinese volunteers were enrolled and divided into 3 different groups for the clinical trial, evenly male and female. The three groups were administrated by one bolus of 0.5,0.75,1.05mg/kg bivalirudin respectively. 10mL blood samples were obtained at predetermined time points before and after bivalirudin administation, which is 0,5,10,20,30,45,60,80,120,240 min, 3mL of which was used for determining the bivalirudin concentration in plasma, 3ml for assaying the four indicators of blood coagulation ( PT, APTT, TT and FIB), 4ml for monitoring the ACT. The protocol was agreed by ethic committee, and informed consent form was signed by every volunteer. The primary pharmacokinetic parameters were t1/2,C1,Vd,AUC that were caculated using WinNonlin 5.2.1 through non-compartment models , and the relationship of concentration and effect was observed, which ensured the PK/PD feathers of the Bivalirudin.③the pharmacokinetic-pharmacodynamic data from the clinical trial was used to develop PK,PD and PK/PD model by winNonlin 5.2.1 compartment model. The feasibility of the PK/PD model was assayed by comparing the results of model and detection.④According to the clinical demand, by using the developed PK/PD model to simulate the Pharmacokinetic-Pharmacodynamic process of Bivalirudin, the Sequential dosing regimen was designed. 12 healthy Chinese volunteers were selected for the trial and administrated the bivalirudin sequential regimen (0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for 4h). 10mL blood samples were obtained at predetermined time points before and after bivalirudin adminstration, which is 0,10,30,60,120,240,245,250,260,285,300,320,360,480min. which was used to determine the concentration and assay the changes of blood coagulation. Then, by comparing the results of the model with the detection, the feasibility of developed PK/PD model was explored.⑤The signs and symptoms of the research subjects in the single dosing and sequential dosing clinical trial were collected to analyze the safety of the Bivalirudin in Chinese population.⑥SAS 9.1.3 was used to conduct the statistic analysis. Quantitative index includes samples, average and standard deviation. Classification index includes a variety of numbers and percentages. The level of significance is 0.05, if the value of P less than or equal to 0.05 is considered statistically significant. According to different cases, F-test, K-W test or t-test was used.Results①A simple, rapid LC-MS/MS method was developed and validated for the identification and quantification of bivalirudin in human plasma and the specificity,sensitivity, precision, average recovery ratio, stability, dilution effect and matrix effect all satisfied the pharmacokinetic detection requirements. The assay demonstrated linearity from 20 to 20000 ug/L bivalirudin in plasma, with a detection limit of 20 ug/L.②Administrated by one bolus of 0.5,0.75,1.05mg/kg respectively, the main Pharmacodynamic parameters of bivalirudin: t1/2 is 0.41±0.12,0.49±0.18,0.46±0.15 h respectively; Cl is 0.50±0.24,0.38±0.06,0.53±0.24 L/h/kg respectively;Vd is 0.29±0.13,0.26±0.1,0.33±15 L/kg respectively;MRT is 0.37±0.06,0.45±0.12,0.43±0.08h. There is no statistically significant differences within different dosage groups (P>0.05).C0 is 4902.84±4556.64,6495.15±4659.54,6805.62±4130.55μg/L respectively; AUC0～t is 1126.91±352.93,1968.24±359.28,2292.34±903.91h*μg/l respectively,C0,AUC0~t increases in proportion to the increase of doses,and there is no statistically significant differences among C0,AUC0~t of each dose group normalized by dose ( P>0.05). The main Pharmacodynamic parameters of male and femal: t1/2 is 0.48±0.17,0.43±0.13h;Vd is 0.31±0.15,0.28±0.10 L/kg;Cl is 0.48±0.26,0.46±0.14 L/h/kg;MRT is 0.39±0.09,0.35±0.08h. There is no difference between male and femal(P>0.05)。③Bivalirudin administrated by once bolus of 0.5,0.75,1.05mg/kg, the value of ACT reaches the peak at once, and the Emax is 237.13±49.31,244.67±40.52,281.79±31.72 s respectively, time-effect curves and time-concentration curve are paralleled.④According to the stimulating of the bivalirudin compartment model, the value of AIC is minimum in the two-compartment model. The pharmacodynamic model fit the M-M equation model. The parameters of the PK/PD model are as follows: Vc=0.12,k10=3.54,k12=0.75,k21=1.44,E0=126.87,Emax=340.03,EC50=4258.03. all the model value lies in the 95% confidence interval.⑤Sequential dosing of bivalirudin (0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for 4h) the concentration in plasma waved between 3000-4500ug/L, the value of ACT is between 220-240s, the value of PK/PD model lies in the 95% confidence interval too.⑥Most of the signs and the symptoms of the volunteers before and after the single or the sequential dosing of bivalirudin have no statistically significant differences (P>0.05), except Blood pressure decreased 4-5mmHg averagely. During the trials, 5 cases totally appeared adverse events, including 3 cases related with Bivalirudin, with mild mucosal bleeding, all of which were in the sequential group.Conclusions①The developed assay method was successfully applied to a pharmacokinetic (PK) study in healthy volunteers after intravenous administration of bivalirudin.②Administrated by once bolus on Chinese healthy volunteers, the excreting process of Bivalirudin was first-order elimination in the range of 0.5-1.05mg/kg.③Bivalirudin has a fast and short effect, and the drug effect has relation with the concentration in plasma, showing concentration-dependent manners.④Pharmacokinetics of bivalirudin in plasma after intravenous administration were fitted to the two-compartment model with the first-order elimination and pharmacodynamics of bivalirudin was fitted to the M-M equation model. The developed PK/PD model can predict the clinical effect accurately.⑤Sequential dosing (0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for 4h) can meet the clinical demand effectively.⑥Bivalirudin regimen in the range of 0.5~1.05mg/kg or Sequential dosing (0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for 4h) has good safety and tolerance in Chinese population. |
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