Martínez González Javier, Monreal Mayte, Ayani Almagia Ignacio, Llaudó Garín Jordi, Ochoa Díaz de Monasterioguren Lourdes, Gutierro Adúriz Ibón
R&D Department, Laboratorios Farmacéuticos Rovi S.A., Madrid, Spain.
Drug Des Devel Ther. 2018 Mar 19;12:575-582. doi: 10.2147/DDDT.S162817. eCollection 2018.
To demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence of a biosimilar enoxaparin to the reference drug, and to assess its safety and tolerability in healthy volunteers.
A randomized, double-blind, crossover, 2-sequence, single-dose study was conducted in healthy volunteers of both sexes. Participants were sequentially and randomly administered single subcutaneous injections of enoxaparin 100 mg manufactured by Rovi (test; Madrid, Spain) and Clexane (enoxaparin 100 mg manufactured by Sanofi, reference) separated by a 1-week washout period. The primary PK/PD variables were maximum activity (A) and area under the effect curve from time 0 to the last measured activity (T) (AUEC) and AUEC from time 0 to infinity (AUEC) of anti-FXa activity, and A and AUEC of anti-FIIa activity. Secondary variables were A and AUEC, AUEC of tissue factor pathway inhibitor, and the ratio of AUEC anti-FXa to anti-FIIa activity. Biosimilarity would be shown when the 95% CI of the ratio of geometric least squares means (95% CI RGLSMs) of primary PK/PD parameters fell within the standard range of bioequivalence, ie, 80%-125%.
The study sample consisted of 46 volunteers (33 males) aged 18-44 years and with body mass index ranging from 19.0 to 31.1 kg/m. Three subjects did not complete the study. The curves of anti-FXa, anti-FIIa and tissue factor pathway inhibitor activities corresponding to administration of the test and reference products were comparable. The 95% CI RGLSMs of A, AUEC and AUEC for anti-FXa activity were 94.6%-105.9%, 99.8%-108.0% and 100.0%-108.6% respectively; A and AUEC for anti-FIIa activity were 94.7%-112.6% and 90.9%-117.9% respectively. In addition, the 95% CI RGLSMs of all secondary variables fell within the range 80%-125%. The incidence and types of adverse events after administration of the test and reference drugs were similar.
The results conclusively showed that the enoxaparin manufactured by Rovi is equivalent to the reference enoxaparin in all primary and secondary PK/PD parameters, as required by the European Medicines Agency to grant marketing authorization to a biosimilar low molecular-weight heparin.
证明生物类似药依诺肝素与参比药物的药代动力学/药效学（PK/PD）等效性，并评估其在健康志愿者中的安全性和耐受性。
在成年男女健康志愿者中进行了一项随机、双盲、交叉、双序列、单剂量研究。参与者按顺序随机接受由罗维公司（试验药；西班牙马德里）生产的100 mg依诺肝素和克赛（赛诺菲生产的100 mg依诺肝素，参比药）的单次皮下注射，中间间隔1周的洗脱期。主要PK/PD变量为抗Xa因子活性的最大活性（A）、从时间0至最后一次测量活性（T）的效应曲线下面积（AUEC）以及从时间0至无穷大的AUEC，以及抗IIa因子活性的A和AUEC。次要变量为A和AUEC、组织因子途径抑制剂的AUEC，以及抗Xa因子与抗IIa因子活性的AUEC比值。当主要PK/PD参数的几何最小二乘均值比值的95%置信区间（95% CI RGLSMs）落在生物等效性的标准范围内，即80%-125%时，表明具有生物相似性。
研究样本包括46名年龄在18-44岁之间、体重指数在19.0至31.1 kg/m之间的志愿者（33名男性）。三名受试者未完成研究。与试验产品和参比产品给药对应的抗Xa因子、抗IIa因子和组织因子途径抑制剂活性曲线具有可比性。抗Xa因子活性的A、AUEC和AUEC的95% CI RGLSMs分别为94.6%-105.9%、99.8%-108.0%和100.0%-108.6%；抗IIa因子活性的A和AUEC分别为94.7%-112.6%和90.9%-117.9%。此外，所有次要变量的95% CI RGLSMs均落在80%-125%范围内。试验药物和参比药物给药后不良事件的发生率和类型相似。
结果确凿表明，罗维公司生产的依诺肝素在所有主要和次要PK/PD参数方面与参比依诺肝素等效，这是欧洲药品管理局批准生物类似低分子肝素上市许可所要求的。
