恩替卡韦片在中国健康人体中的生物等效性及安全性评价

柳正植; 高振月; 任庆; 霍丹丹; 杨海淼

doi:10.3969/j.issn.1001-5256.2020.12.011

恩替卡韦片在中国健康人体中的生物等效性及安全性评价

DOI: 10.3969/j.issn.1001-5256.2020.12.011

1. 长春中医药大学附属医院Ⅰ期临床试验研究室
2. 正大天晴药业集团股份有限公司临床中心

详细信息

中图分类号: R969
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出版历程
- 收稿日期: 2020-09-08
- 出版日期: 2020-12-20

Bioequivalence and safety of entecavir tablets in healthy Chinese subjects

Institute of Phase I Clinical Trial,The Affiliated Hospital of Changchun University of Chinese Medicine
Clinical Center,Chia Tai Tianqing Pharmaceutical Group Co.,Ltd.

摘要

摘要:
目的评价恩替卡韦仿制药与原研药恩替卡韦片在中国健康受试者中的生物等效性及安全性。方法纳入28例健康受试者,采用随机、开放、两周期、两交叉、空腹状态下的试验设计,两周期分别单次口服受试制剂或参比制剂各0. 5 mg,采用液相色谱串联质谱法（LC-MS/MS）测定服药后72 h内16个不同时间点的血药浓度,计算主要药代动力学参数Cmax、AUC0-t和AUC0-∞评价其生物等效性。采用WinNonlin软件计算药代动力学参数,并进行生物等效性评价。结果空腹状态下口服受试制剂和参比制剂后,主要药动学参数Cmax、AUC0-t和AUC0-∞几何均数的比值分别为98. 18%、101. 97%、103. 07%,90%可信区间分别为91. 36%～105. 50%,98. 32%～105. 74%,96. 30%～110. 32%,均在80. 00%～125. 00%之间。对药代动力学参数Cmax、AUC0-t、AUC0-∞经自然对数转换后,进行方差分析,结果显示空腹状态下给药周期间差异（P<0. p="">0. 05）符合生物等效性判定标准,且在试验过程...
- 乙型肝炎 /
- 恩替卡韦 /
- 治疗等效 /
- 串联质谱法
Abstract:
Objective To investigate the bioequivalence and safety of the generic drug entecavir versus the original drug entecavir tablets in healthy Chinese subjects. Methods A randomized,open,two-cycle,two-cross,fasting trial was designed and performed for 28 healthy subjects,and the subjects were given single oral administration of the test preparation or the reference preparation at a dose of 0. 5 mg in the two cycles,respectively. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentration at 16 different time points within 72 hours after administration,and the main pharmacokinetic parameters Cmax,AUC0-t,and AUC0-∞were calculated to evaluate bioequivalence. WinNonlin software was used to calculate pharmacokinetic parameters and perform bioequivalence evaluation. Results After the oral administration of the test preparation or the reference preparation in the fasting state,the main geometric means( 90% confidence interval) of the main pharmacokinetic parameters Cmax,AUC0-t,and AUC0-∞were 98. 18%( 91. 36%-105. 50%),101. 97%( 98. 32%-105. 74%),and 103. 07%( 96. 30%-110. 32%),respectively,all of which were within the range of 80. 00%-125. 00%.After the pharmacokinetic parameters Cmax,AUC0-t,AUC0-∞were transformed by natural logarithm,the variance analysis was carried out. The P value test results showed that the difference between the dosing weeks( P < 0. 05),the dosing sequence and differences in formulation factors( P > 0. 05). Meet the criteria of bioequivalence. Conclusion The two preparations are bioequivalent and have good safety in healthy Chinese subjects.
- hepatitis B /
- entecavir /
- therapeutic equivalency /
- tandem mass spectrometry

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参考文献(20)

[1] SCHWEITZER A,HORN J,MIKOLAJCZYK RT,et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection:A systematic review of data published between 1965 and2013[J]. Lancet,2015,386(10003):1546-1555.

[2] MCCLUNE AC,TONG MJ. Chronic hepatitis B and hepatocellular carcinoma[J]. Clin Liver Dis,2010,14(3):461-476.

[3] ZOULIM F. Hepatitis:Treatment failure in chronic hepatitis B[J]. Nat Rev Gastroenterol Hepatol,2011,8(7):366-367.

[4] MATTHEWS SJ. Entecavir for the treatment of chronic hepatitis B virus infection[J]. Clin Ther,2006,28(2):184-203.

[5] HONKOOP P,DE MAN RA. Entecavir:A potent new antiviral drug for hepatitis B[J]. Expert Opin Investig Drugs,2003,12(4):683-688.

[6] LANGLEY DR,WALSH AW,BALDICK CJ,et al. Inhibition of hepatitis B virus polymerase by entecavir[J]. J Virol,2007,81(8):3992-4001.

[7] RIVKIN A. Entecavir:A new nucleoside analogue for the treatment of chronic hepatitis B[J]. Drugs Today(Barc),2007,43(4):201-220.

[8] CHENG PN,CHANG TT. Entecavir:A potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients[J]. Expert Rev Anti Infect Ther,2008,6(5):569-579.

[9] TAO JX,LI XD,CAO T,et al. A study of compliance in patients with HBe Ag-negative chronic hepatitis B receiving entecavir treatment[J]. J Clin Hepatol,2017,33(8):1558-1560.(in Chinese)陶军秀，李晓东，曹婷，等．恩替卡韦治疗HBe Ag阴性慢性乙型肝炎患者的依从性调查[J]．临床肝胆病杂志，2017,33(8):1558-1560.

[10] ZHAO Y,LI Y,QI L,et al. Antiviral curative effects of tenofovir and entecavir in treatment of aged patients with chronic hepatitis B and their regulation on inflammation factors[J]. J Jilin Univ(Med Edit),2019,45(1):117-122.(in Chinese)赵阳，李烨，齐玲，等．替诺福韦酯和恩替卡韦治疗老年慢性乙型肝炎患者的抗病毒疗效及对致炎细胞因子的调节作用[J]．吉林大学学报(医学版)，2019,45(1):117-122.

[11] LI ZH,ZHANG XL,GUO YQ,et al. Effect of Anluohuaxian Pills combined with Entecavir in the treatment of hepatitis B cirrhosis and its influence on liver function[J]. China Med Herald,2020,17(28):151-154.(in Chinese)李朝晖，张晓龙，郭彦清，等．安络化纤丸联合恩替卡韦治疗乙肝肝硬化的效果及对肝功能的影响[J]．中国医药导报，2020,17(28):151-154.

[12] ZHENG MH,SHI KQ,DAI ZJ,et al. A 24-week,parallelgroup,open-label,randomized clinical trial comparing the early antiviral efficacy of telbivudine and entecavir in the treatment of hepatitis B e antigen-positive chronic hepatitis B virus infection in adult Chinese patients[J]. Clin Ther,2010,32(4):649-658.

[13] GUO JJ,LI QL,SHI XF,et al. Dynamics of hepatitis B virus resistance to entecavir in a nucleoside/nucleotide-nave patient[J]. Antiviral Res,2009,81(2):180-183.

[14] CHENG PN,CHANG TT. Entecavir:A potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients[J]. Expert Rev Anti Infect Ther,2008,6(5):569-579.

[15] MATTHEWS SJ. Entecavir for the treatment of chronic hepatitis B virus infection[J]. Clin Ther,2006,28(2):184-203.

[16] YAN JH,BIFANO M,OLSEN S,et al. Entecavir pharmacokinetics,safety,and tolerability after multiple ascending doses in healthy subjects[J]. J Clin Pharmacol,2006,46(11):1250-1258.

[17] Center For Drug Evaluation. Technical guidelines for the bioequivalence study of generic chemincal drugs with pharmacokinetics parameters as the final evaluation index[S/OL].[2015-11-17]. http://www. cde. org. cn/zdyz. do? method=largePage&id=353342c97683d4fb. pdf.(in Chinese)国家药品监督管理局药品审评中心．以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则[S/OL].[2015-11-17]. http://www. cde. org. cn/zdyz. do?method=largePage&id=353342c97683d4fb. pdf.

[18] US The Food and Drug Administration. Guidance for industry:Bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA draft guidance[S/OL].[2014-06-16]. http://www. fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM377465. pdf.

[19] IQBAL M,EZZELDIN E,AL-RASHOOD KA,et al. Rapid determination of canagliflozin in rat plasma by UHPLC-MS/MS using negative ionization mode to avoid adduct-ions formation[J]. Talanta,2015,132:29-36.

[20] ZHU M,BIFANO M,XU X,et al. Lack of an effect of human immunodeficiency virus coinfection on the pharmacokinetics of entecavir in hepatitis B virus-infected patients[J]. Antimicrob Agents Chemother,2008,52(8):2836-2841.

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