Kobbi Zina, Kraiem Hazar, Benlasfar Zakaria, Marouani Ammar, Massoud Taieb, Boubaker Samir, Bouhaouala-Zahar Balkiss, Fenina Nadia
Faculty of Pharmacy of Monastir, Rue Ibn Sina, 5000, University of Monastir, Tunisia.
Laboratory of Venoms and Therapeutic Molecules, Pasteur Institute of Tunis, 13 Place Pasteur, BP74, 1002, Tunis, University of Tunis El Manar, Tunisia.
Regul Toxicol Pharmacol. 2017 Mar;84:9-17. doi: 10.1016/j.yrtph.2016.12.003. Epub 2016 Dec 10.
Enoxaparin is a low-molecular-weight heparin widely used for the prevention and treatment of thromboembolism. With the development of several enoxaparin biosimilars, real medical concerns about their safety and efficacy have been raised. This repeated dose toxicity study consists of preclinical toxicological evaluation of a biosimilar biological version of enoxaparin, the drug product "Enoxa", compared to the enoxaparin reference drug product, "Lovenox". Eighty white Wistar rats were treated with "Enoxa" versus the reference product, using subcutaneous therapeutic and toxic doses, varying from 3.5 to 100 mg/kg/day. Dose levels were adjusted and ultimately fixed at 3.5 and 20 mg/kg/day as therapeutic and toxic doses, respectively. A sodium chloride solution (0.9%) was used as the control, and the comparative study was conducted over periods of 14 and 28 days. Comparable effects were observed with few adverse effects at the administration dose of 20 mg/kg/day, for both enoxaparin biosimilar and reference products. Interestingly, mortality started only at high doses of 40 mg/kg/day and reached 25% at 100 mg/kg/day for both products. These results, as part of the recommended biosimilarity monitoring, demonstrated comparable toxicity profiles of "Enoxa" and "Lovenox" products in rats. Continuing investigation of biosimilarity on humans to confirm safety and efficacy is suggested.
依诺肝素是一种广泛用于预防和治疗血栓栓塞的低分子量肝素。随着几种依诺肝素生物类似药的研发，人们对其安全性和有效性产生了实际的医学担忧。这项重复给药毒性研究包括对依诺肝素生物类似药“Enoxa”与依诺肝素参比药品“Lovenox”进行临床前毒理学评估。80只白色Wistar大鼠分别接受“Enoxa”或参比产品皮下给药，治疗剂量和毒性剂量范围为3.5至100mg/kg/天。剂量水平经调整后最终确定为治疗剂量3.5mg/kg/天和毒性剂量20mg/kg/天。使用氯化钠溶液（0.9%）作为对照，比较研究为期14天和28天。在20mg/kg/天的给药剂量下，依诺肝素生物类似药和参比产品均观察到类似效应，且不良反应较少。有趣的是，两种产品均仅在40mg/kg/天的高剂量下开始出现死亡，在100mg/kg/天的剂量下死亡率达到25%。这些结果作为推荐的生物相似性监测的一部分，证明了“Enoxa”和“Lovenox”产品在大鼠中的毒性特征相似。建议继续对人体进行生物相似性研究以确认安全性和有效性。
