国产达肝素钠注射液在健康受试者的生物等效性及安全性
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摘要
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 pharmacokinetic behaviors and bioequivalence of two kinds of dalteparin sodium injections after subcutaneous injection in healthy Chinese volunteers. Methods: A single-dose,randomized,open label,two way crossover study was designed to evaluate the bioequivalence and safety of domestic dalteparin sodium injection in healthy Chinese male volunteers under fasting condition. Twenty-six volunteers were recruited,including 2 for pilot trial,and 24 for formal trial. The subjects were divided into two groups randomly and subcutaneously administered respectively with single dose of test or reference preparation of dalteparin sodium injection( 0. 2 m L∶ 5 000 IU). Blood samples were collected at preset time. The wash-out period was one week.Emax,AUEC_(0~t) and AUEC_(0~∞)were calculated by non-compartmental analysis,and the 90% confidence intervals( CIs) of the ratios between the test and reference preparations were assessed. The safety profile was evaluated by adverse events( AEs) record,and assessed by physical examination,vital signs and clinical laboratory results. All the 26 subjects were included in the safety set( SS) and the 24 subjects in the formal trial were brought into per-protocol set( PPS). Results: All of the 26 subjects completed this trial. The 90% CIs for the ratios of EmaxandAUEC0 ~ tof AT Ⅱ a were 95. 36% ~ 111. 77%,83. 80% ~ 110. 15% and those of ATXa were 101. 50% ~114. 30%,103. 57% ~ 116. 46%,respectively. The above-mentioned values met the predetermined criteria for assuming bioequivalence. Eight subjects reported a total of 10 mild AEs( 3 reported by 3 subjects who received the test preparation,and 7 reported by 6 subjects who received the reference preparation). No serious adverse events( SAEs) were observed. Conclusion: In this single-dose study,the test and reference preparations of dalteparin sodium injection met the regulatory definition for assuming bioequivalence in Chinese healthy male volunteers. The domestic preparation is generally well tolerated in the test population.
Objective: To evaluate the pharmacokinetic behaviors and bioequivalence of two kinds of dalteparin sodium injections after subcutaneous injection in healthy Chinese volunteers. Methods: A single-dose,randomized,open label,two way crossover study was designed to evaluate the bioequivalence and safety of domestic dalteparin sodium injection in healthy Chinese male volunteers under fasting condition. Twenty-six volunteers were recruited,including 2 for pilot trial,and 24 for formal trial. The subjects were divided into two groups randomly and subcutaneously administered respectively with single dose of test or reference preparation of dalteparin sodium injection( 0. 2 m L∶ 5 000 IU). Blood samples were collected at preset time. The wash-out period was one week.Emax,AUEC_(0~t) and AUEC_(0~∞)were calculated by non-compartmental analysis,and the 90% confidence intervals( CIs) of the ratios between the test and reference preparations were assessed. The safety profile was evaluated by adverse events( AEs) record,and assessed by physical examination,vital signs and clinical laboratory results. All the 26 subjects were included in the safety set( SS) and the 24 subjects in the formal trial were brought into per-protocol set( PPS). Results: All of the 26 subjects completed this trial. The 90% CIs for the ratios of EmaxandAUEC0 ~ tof AT Ⅱ a were 95. 36% ~ 111. 77%,83. 80% ~ 110. 15% and those of ATXa were 101. 50% ~114. 30%,103. 57% ~ 116. 46%,respectively. The above-mentioned values met the predetermined criteria for assuming bioequivalence. Eight subjects reported a total of 10 mild AEs( 3 reported by 3 subjects who received the test preparation,and 7 reported by 6 subjects who received the reference preparation). No serious adverse events( SAEs) were observed. Conclusion: In this single-dose study,the test and reference preparations of dalteparin sodium injection met the regulatory definition for assuming bioequivalence in Chinese healthy male volunteers. The domestic preparation is generally well tolerated in the test population.
引文
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[3]HIRSH J,BAUER KA,DONATI MB,et al.Parenteral anticoagulants:American college of chest physicians evidence-based clinical practice guidelines(8th edition)[J].Chest,2008,133(6Suppl):141S-159S.
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[5]Fragmin[prescribing information].NY:Pfizer Inc.;Germany:Vetter Pharma-Fertigung[EB/OL].2010.http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020287s050lbl.pdf.
[6]FEJGIN MD,LOURWOOD DL.Low molecular weight heparins and their use in obstetrics and gynecology[J].Obstet Gynecol Surv,1994,49(6):424-431.
[7]GADIKO C,TIPPABHOTLA SK,THOTA S,et al.Bioequivalence study of two subcutaneous formulations of dalteparin:randomized,singledose,two-sequence,two-period,cross-over study in healthy voluteers[J].J Drug Assess,2013,2(1):21-29.