| BACKGROUNDVenous thromboembolism (VTE) was the common complication of tumor and surgery, which could result in life-threatening pulmonary embolism (PE). The purpose of VTE therapy was to prevent and reduce the incidence and mortality, prevent the recurrence of thrombosis, reduce the incidence rate of post-thrombosis syndrome (PTS). Anticoagulant therapy was the core and basis of VTE therapy. Fondaparinux sodium, a chemosynthetic anticoagulant, selective factor Xa inhibitor, was approved to prevent the VTE in high-risk patients. There was no literature on fondaparinux sodium’s pharmacokinetics of Chinese population. This research was focus on the pharmacokinetic features of the patients who were subcutaneously injected fondaparinux sodium2.5mg after thoracic surgery. Evaluate the relativity between the patients’clinical efficacy indicators and the pharmacokinetic parameters by observing the change of TEG and coagulant indicators both before and after the drug use, as well as the safety of the drug use. So that it could provide the evidence to determine the therapeutic dose for Chinese patients.AIMS:1. To establish a method to detect the concentration of fondaparinux sodium in human plasma.2. To study the pharmacokinetic characteristics in Chinese thoracic surgery patients and to evaluate the correlation between patients’ general state and the pharmacokinetic parameters.3. To evaluate the relativity between the patients’clinical effect indicators and the pharmacokinetic parameters by observing the change of TEG and coagulant indicators both before and after the drug use, as well as the safety and tolerance in Chinese.METHODS:1. The heparin kit was used to fit the standard curve, measure the limit of detection, precision, recovery rate and stability.2. According to the inclusive and exclusive criteria,13patients were recruited. A single dose of2.5mg fondaparinux sodium was administered subcutaneously not less than6hours after operation. Collected blood samples (1.5mL) from each patient before the administration and at20,40min,1,1.5,2,3,4,6,8,12,24h after the first dose, and3h after the second and the third dose. The drug concentration of the plasma samples was determined. Basing on the first dose plasma concentration, fitted the noncompartmental model by using WinNonLin6.21software and calculated the pharmacokinetic parameters. Bivariate correlation analysis was analyzed between the pharmacokinetic parameters and the patients’ general states, and paired-sample t test of the plasma concentration of multiple doses by the software SPSS16.0.3. This was a prospective observational clinical trial. The inclusive criteria and administration were the same as the former study. The patients should be taken coagulation function test and thrombelastography(TEG) before administration. The first, second and third day morning after drug dosing, the patients should be taken coagulation function test at6am and detect the TEG and plasma concentration of fondaparinux sodium at10am. Documented the amount of pleural fluid and detected the red-cell count of pleural fluid as well. The patients’temperature, heart rate, blood pressure, respiratory rate, hepatorenal function, blood albumin, blood regular test, and blood glucose before and after the administration were documented. The clinical indicators before and after the administration were performed paired-sample t test. Bivariate correlation analysis was used to calculate correlation between pharmacokinetic parameters and TEG parameters and the difference value of TEG parameters before and after drug use separately. Bivariate correlation analysis was used to study correlation between the drug plasma concentration and the corresponding TEG parameters. Bivariate correlation analysis was used to analyze correlation between TEG parameters and the amount of pleural fluid and the red-cell count of the pleural fluid separately of the first day.RESULTS:1. The linearity of the standard curve was preferable ranged from0.1to1.5mg·L-1. The limit of detection was0.1mg·L-1. The intra-and inter-assay relative standard deviation (RSD) was4.2～8.44%and2.73～9.51%, respectively. The method recovery rate was99.5～102%.2. The following pharmacokinetic parameters were derived:t1/2,z7.92±3.13(4.21-15.89) h; tmax2.52±0.93(1.38-4) h,Cmax0.73±0.18(0.45-1.02) mg·L-1; AUClast6.56±2.19(3.07-9.75)h·mg·L-1; Vz/f3.54±1.00(2.24-5.73) L; Cl/f0.34±0.14(0.16～0.63) L·h-1. The Pearson correlation, r, was0.73(p=0.005) by evaluated the correlation between the serum creatinine and mean residence time (MRTlast) of fondaparinux sodium.3. Compared with pre-treatment, there was significant difference in:"R" time of the first and second day after administration (P<0.05), FIB of the first, second and third day after administration (P<0.01), PT and INR of the first day after administration (P<0.01), and D-dimer of the second and third day after administration. The rest indicators had no significant difference. There was no correlation between the drug plasma concentration of TEG and TEG parameters. There was no correlation between the pharmacokinetic parameters and TEG parameters, the amount of pleural fluid and red-cell count of pleural fluid of the first day. During the period of study, no patient had mucous membrane hemorrhage, FOB(+), drug-related dizzy, headache and nausea, and massive hemorrhage. The liver function indicators were slight increased and the blood albumin were decreased after administration. There were no clinical interfere to treat the ADEs and the patients’abnormal clinical indexs went to normal up to7days.CONCLUSION:This study had established the method, which was qualified for the methodology of pharmacokinetic research, to detect the blood plasma concentration of fondaparinux sodium. A statistical correlation between the Scr and MRTlast of fondaparinux sodium was observed. Fondaparinux sodium can prolong the "R" time of TEG, reduce D-dimer level and not influence the in vitro coagulant index. There is no statistical correlation between the pharmacokinetic parameters and the clinical efficacy indicators. Fondaparinux sodium has good tolerance in Chinese thoracic surgery patients. |
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