Oliveira Stephan-Nicollas M C G, Santos Gustavo R C, Glauser Bianca F, Capillé Nina V M, Queiroz Ismael N L, Pereira Mariana S, Pomin Vitor H, Mourão Paulo A S
Paulo A. S. Mourão, Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Caixa Postal 68041, Rio de Janeiro, RJ, 21941-590, Brazil, Tel./Fax: +55 21 3938 2090, E-mail:
Thromb Haemost. 2015 Jan;113(1):53-65. doi: 10.1160/TH14-05-0411. Epub 2014 Sep 25.
Biosimilar enoxaparins have been available for clinical use in Brazil since 2009. Although their use has reduced costs of treatment expenses, their implementation still raises some concerns about efficiency, safety, regularity and reproducibility of batches. We undertook structural and functional analyses on over 90 batches of pharmaceutical-active ingredient, and 330 ones of the final products of biosimilar enoxaparins available in the Brazilian market between 2009 and 2014. Besides a nationwide-scale analysis, we have also employed methods that go beyond those recommended by the standard pharmacopeias. We have used high-resolution 2D NMR, detailed assessment of the anticoagulant and antithrombotic properties, check of side effects in experimental animals after continuous administration, and analyses of individual composing oligosaccharides. The 1D 1H NMR spectra of all batches of biosimilar enoxaparins are fairly coincident, and the resultant average spectrum is quite identical to that from the original drug. This structural equality was also assured by highly resolved 2D NMR spectra. The anticoagulant activity, determined by diverse assays and the in vivo antithrombotic and bleeding effects of the biosimilar version were confirmed as equal as of the parental enoxaparins. Structure and function of the composing oligosaccharides were identical in both enoxaparin types. No side effect was observed after continuous subcutaneous administration to rats for 30 days at the dose of 2 mg kg⁻¹ body weight. Biosimilar enoxaparins available in Brazil fulfilled the requirement of the five items defined by FDA-USA for approval of this type of drug.
自2009年起，生物类似药依诺肝素已在巴西临床应用。尽管其使用降低了治疗费用，但在实施过程中，人们仍对批次的效率、安全性、规律性和可重复性存在一些担忧。我们对2009年至2014年间巴西市场上90多批药物活性成分以及330批生物类似药依诺肝素的最终产品进行了结构和功能分析。除了全国范围的分析，我们还采用了超出标准药典推荐的方法。我们使用了高分辨率二维核磁共振、对抗凝和抗血栓特性的详细评估、连续给药后实验动物副作用的检查以及对单个组成寡糖的分析。所有批次生物类似药依诺肝素的一维氢核磁共振谱相当一致，所得平均谱与原研药物的谱非常相似。高分辨率二维核磁共振谱也确保了这种结构上的一致性。通过多种测定方法确定的生物类似药版本的抗凝活性以及体内抗血栓和出血作用被证实与原研依诺肝素相当。两种依诺肝素类型中组成寡糖的结构和功能相同。以2 mg kg⁻¹体重的剂量对大鼠连续皮下给药30天，未观察到副作用。巴西市场上的生物类似药依诺肝素符合美国食品药品监督管理局（FDA）批准此类药物所定义的五项要求。
