依那西普预充液与复溶冻干粉注射液的生物等效性研究
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摘要
目的确证依那西普预充液(PFS~?)和复溶冻干粉注射液(LYO~?)的生物等效性,并评估依那西普PFS在中国健康男性受试者中的安全性和耐受性。方法一项随机、开放、双向交叉设计的研究,共纳入50位健康受试者。在受试者腹部皮下单次注射50 mg的依那西普PFS~?(受试组)或LYO~?(参比组)后,评估2组间的生物等效性。连续收集受试者用药后2周内的血液样本,用酶联免疫吸附实验测定血清样本中依那西普的浓度,用标准非房室模型法计算药代动力学参数。主要研究终点为初始至终末采血时间点内的浓度-时间曲线下面积(AUC_(last))和血清峰浓度(C_(max))。结果 50名受试者中有48名完成研究。受试组与参比组AUC_(last)和C_(max)的校正几何平均数比例(90%的置信区间)分别为119.2%(114.1%～124.6%)和115.8%(109.6%～122.4%),完全位于己制定的80%～125%的生物等效性范围内。在本研究中,2种剂型的依那西普均是安全的,具有良好的耐受性。结论在中国健康受试者腹部皮下注射等量的依那西普时,PFS~?和LYO~?剂型间具有生物等效性。由此预测,等剂量的2种剂型具有同等的治疗效果,可以互换使用。
Objective To establish the bioequivalence between etanercept prefilled syringe(PFS~?)and reconstituted lyophilized powder for injection(LYO~?)dosage forms and to evaluate the safety and tolerability of etanercept in healthy Chinese male subjects.Methods This randomized, open-label,two-way crossover study in 50 healthy subjects evaluated the bioequivalence between the etanercept PFS~?(test)and the LYO~?(reference)formulations following single 50 mg subcutaneous injections in the abdomen.Serial pharmacokinetic blood samples were collected for up to two weeks postdose and serum specimens were analyzed for etanercept using an enzyme-linked immunosorbent assay.Pharmacokinetic parameters were determined using standard non-compartmental methods.The p rimary endpoints were area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration(AUC_(last))and maximum serum concentration(C_(max)).Results Of the 50 sub jects enrolled 48 subjects completed the study.The 90% confidence intervals for the ratios of adjusted geometric means of AUClast and Cmax were 119.2%(114.1%,124.6%)and 115.8%(109.6%,122.4%),respectively,between the test and reference formulations and were completely contained within the established bioequivalence limits of 80% to 125%.The two etanercept formulations were safe and well tolerated in this study.Conclusion Etanercept PFS~? was bioequivalent to the LYO~? dosage form at an equivalent dose when administered sub cutaneous injections in the abdomen of healthy Chinese sub jects.At equivalent doses,both formulations are anticipated to be therapeutically equivalent and treatment could be switched between these two dosage forms.
Objective To establish the bioequivalence between etanercept prefilled syringe(PFS~?)and reconstituted lyophilized powder for injection(LYO~?)dosage forms and to evaluate the safety and tolerability of etanercept in healthy Chinese male subjects.Methods This randomized, open-label,two-way crossover study in 50 healthy subjects evaluated the bioequivalence between the etanercept PFS~?(test)and the LYO~?(reference)formulations following single 50 mg subcutaneous injections in the abdomen.Serial pharmacokinetic blood samples were collected for up to two weeks postdose and serum specimens were analyzed for etanercept using an enzyme-linked immunosorbent assay.Pharmacokinetic parameters were determined using standard non-compartmental methods.The p rimary endpoints were area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration(AUC_(last))and maximum serum concentration(C_(max)).Results Of the 50 sub jects enrolled 48 subjects completed the study.The 90% confidence intervals for the ratios of adjusted geometric means of AUClast and Cmax were 119.2%(114.1%,124.6%)and 115.8%(109.6%,122.4%),respectively,between the test and reference formulations and were completely contained within the established bioequivalence limits of 80% to 125%.The two etanercept formulations were safe and well tolerated in this study.Conclusion Etanercept PFS~? was bioequivalent to the LYO~? dosage form at an equivalent dose when administered sub cutaneous injections in the abdomen of healthy Chinese sub jects.At equivalent doses,both formulations are anticipated to be therapeutically equivalent and treatment could be switched between these two dosage forms.
引文
[1]中华医学会风湿病学分会.类风湿关节炎诊断及治疗指南[J].中华风湿病学杂志,2010,14(4):265-270.
[2]中华医学会风湿病学分会.强直性脊柱炎诊断及治疗指南[J].中华风湿病学杂志,2010,14(8):557-559.
[3]KORTH-BRADLEY J M,RUBIN A S,HANNA R K,et al.The pharmacokinetics of etanercept in healthy volunteers[J].Ann Pharmacother,2000,34(2):161-164.
[4]ZHOU H.Clinical pharmacokinetics of etanercept:A fully humanized soluble recombinant tumor necrosis factor receptor fusion protein[J].J Clin Pharmacol,2005,45(5):490-497.
[5]YIM D S,ZHOU H,BUCKWALTER M,et al.Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis[J].J Clin Pharmacol,2005,45(3):246-256.
[6]ZHOU H,BUCKWALTER M,BONI J,et al.Population-based pharmacokinetics of the soluble TNFr etanercept:A clinical study in43 patients with ankylosing spondylitis compared with post hoc data from patients with rheumatoid arthritis[J].Int J Clin Pharmacol Ther,2004,42(5):267-276.
[7]NESTOROV I,ZITNIK R,DEVRIES T,et al.Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis[J].Br J Clin Pharmacol,2006,62(4):435-445.
[8]ELEWSKI B,LEONARDI C,GOTTLIEB A B,et al.Comparison of clinical and pharmacokinetic profiles of etanercept 25 mg twice weekly and 50 mg once weekly in patients with psoriasis[J].Br JDermatol,2007,156(1):138-142.
[9]LEE H,KIMKO H,ROGGE M,et al.Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis[J].Clin Pharmacol Ther,2003,73(4):348-365.
[10]KAWAI S,SEKINO H,YAMASHITA N,et al.The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects[J].J Clin Pharmacol,2006,46(4):418-423.
[11]FANY Y,LI L J,WANY R,et al.Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis[J].Acta Pharmacologica Sinica,2010,31(11):1500-1507.
[12]GU N,YI S,KIM T E,et al.Comparative pharmacokinetics and tolerability of branded etanercept(25 mg)and its biosimilar(25mg):a randomized,open-label,single-dose,two-sequence,crossover study in healthy Korean male volunteers[J].Clin Ther,2011,33(12):2029-2037.
[2]中华医学会风湿病学分会.强直性脊柱炎诊断及治疗指南[J].中华风湿病学杂志,2010,14(8):557-559.
[3]KORTH-BRADLEY J M,RUBIN A S,HANNA R K,et al.The pharmacokinetics of etanercept in healthy volunteers[J].Ann Pharmacother,2000,34(2):161-164.
[4]ZHOU H.Clinical pharmacokinetics of etanercept:A fully humanized soluble recombinant tumor necrosis factor receptor fusion protein[J].J Clin Pharmacol,2005,45(5):490-497.
[5]YIM D S,ZHOU H,BUCKWALTER M,et al.Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis[J].J Clin Pharmacol,2005,45(3):246-256.
[6]ZHOU H,BUCKWALTER M,BONI J,et al.Population-based pharmacokinetics of the soluble TNFr etanercept:A clinical study in43 patients with ankylosing spondylitis compared with post hoc data from patients with rheumatoid arthritis[J].Int J Clin Pharmacol Ther,2004,42(5):267-276.
[7]NESTOROV I,ZITNIK R,DEVRIES T,et al.Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis[J].Br J Clin Pharmacol,2006,62(4):435-445.
[8]ELEWSKI B,LEONARDI C,GOTTLIEB A B,et al.Comparison of clinical and pharmacokinetic profiles of etanercept 25 mg twice weekly and 50 mg once weekly in patients with psoriasis[J].Br JDermatol,2007,156(1):138-142.
[9]LEE H,KIMKO H,ROGGE M,et al.Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis[J].Clin Pharmacol Ther,2003,73(4):348-365.
[10]KAWAI S,SEKINO H,YAMASHITA N,et al.The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects[J].J Clin Pharmacol,2006,46(4):418-423.
[11]FANY Y,LI L J,WANY R,et al.Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis[J].Acta Pharmacologica Sinica,2010,31(11):1500-1507.
[12]GU N,YI S,KIM T E,et al.Comparative pharmacokinetics and tolerability of branded etanercept(25 mg)and its biosimilar(25mg):a randomized,open-label,single-dose,two-sequence,crossover study in healthy Korean male volunteers[J].Clin Ther,2011,33(12):2029-2037.