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目的:评价健康成年男性受试者单次腹壁皮下注射达肝素钠后的生物等效性和安全性。方法:本研究共选择健康受试者26例,2例参与预试验,24例纳入正式试验。试验采用随机、开放、单剂量、双周期交叉设计对国产达肝素钠注射液进行评价,受试者随机分为2组,第1周期分别皮下注射受试制剂或参比制剂,第2周期交叉给药,2个周期间隔时间7 d。受试者禁食过夜至少10 h后分别于腹壁皮下注射受试制剂或参比制剂0.2 m L∶5 000 IU,并于预定时间点采集血样。non-compartmental analysis法计算主要药动学参数:达肝素钠抗Xa和IIa因子E_(max),AUEC_(0~t),AUEC_(0~E),计算受试/参比制剂的90%置信区间。试验过程中行生命体征、实验室及心电图检查,并记录不良事件情况。26例受试者全部纳入安全分析集,24例正式试验者纳入符合方案集。结果:26例志愿者均完成试验。受试与参比制剂抗IIa因子的E_(max),AUEC_(0~t)比值90%置信区间分别在95.36%~111.77%,83.80%~110.15%,抗Xa因子的E_(max),AUEC_(0~t)比值90%置信区间分别在101.50%~114.30%,103.57%~116.46%。上述数据满足生物等效发生标准。试验过程中有8例受试者共发生10例次不良事件。其中,受试制剂发生不良事件3例次,参比制剂发生不良事件7例次。不良事件均为轻度,未发现严重不良事件。结论:国产达肝素钠注射液与参比制剂等效,安全性和耐受性良好。
OBJECTIVE: To evaluate the bioequivalence and safety of dalteparin injected into a single abdominal wall in healthy adult male subjects. METHODS: Totally 26 healthy subjects were selected, 2 were involved in the pre-test, and 24 were included in the formal trial. The randomized, open, single-dose, double-cycle crossover design was used to evaluate domestic dalteparin sodium injection. The subjects were randomly divided into two groups. The first cycle was subcutaneously injected with the test preparation or the reference preparation, the second cycle was crossed Administration, 7-day interval between two cycles. Subjects were subcutaneously injected subcutaneously with test preparations or reference preparations 0.2 m L: 5000 IU at least 10 h after fasted overnight, and blood samples were taken at predetermined time points. The non-compartmental analysis method was used to calculate the main pharmacokinetic parameters: dalteparin sodium anti-Xa and factor Ha (max), AUEC_ (0 ~ t) and AUEC_ (0 ~ E) Range. During the test, vital signs, laboratory and electrocardiographic examination were performed, and the adverse events were recorded. Twenty-six subjects were fully included in the safety analysis set, and 24 formal participants included in the compliance set. Results: Twenty-six volunteers completed the experiment. The 90% confidence intervals of the E_ (max) and AUEC_ (0 ~ t) ratios of anti-factor IIa to test and reference preparations were 95.36% -111.77% and 83.80% -110.15%, respectively. The values of E_max and AUEC_ (0 ~ t) ratio of 90% confidence interval were 101.50% ~ 114.30%, 103.57% ~ 116.46%. The above data meet the bioequivalence criteria. A total of 10 adverse events occurred in 8 subjects during the trial. Among them, 3 cases of adverse events occurred in the test preparations and 7 cases of adverse events in the reference preparations. Adverse events were mild, no serious adverse events were found. Conclusion: The domestic dalteparin sodium injection is equivalent to the reference formulation with good safety and tolerability.