title: Comparative subcutaneous repeated toxicity study of enoxaparin products in rats.
abstract: 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.
authors.affiliation: Faculty of Pharmacy of Monastir, Rue Ibn Sina, 5000, University of Monastir, Tunisia. Electronic address: kobbizina@yahoo.fr.
authors.forename: Zina
authors.initials: Z
authors.lastname: Kobbi
authors.affiliation: Laboratory of Venoms and Therapeutic Molecules, Pasteur Institute of Tunis, 13 Place Pasteur, BP74, 1002, Tunis, University of Tunis El Manar, Tunisia. Electronic address: hazar.kraiem@yahoo.fr.
authors.forename: Hazar
authors.initials: H
authors.lastname: Kraiem
authors.affiliation: Animal Unit, Pasteur Institute of Tunis, 13 Place Pasteur, BP74, 1002, Tunis, University of Tunis El Manar, Tunisia. Electronic address: zakaria.benlasfar@pasteur.rns.tn.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Benlasfar
authors.affiliation: Animal Unit, Pasteur Institute of Tunis, 13 Place Pasteur, BP74, 1002, Tunis, University of Tunis El Manar, Tunisia. Electronic address: ammar.marouani@pasteur.rns.tn.
authors.forename: Ammar
authors.initials: A
authors.lastname: Marouani
authors.affiliation: Laboratory of Biochemistry, Children's Hospital of Tunis/ Faculty of Pharmacy of Monastir, Rue Ibn Sina, 5000, University of Monastir, Tunisia.
authors.forename: Taieb
authors.initials: T
authors.lastname: Massoud
authors.affiliation: Laboratory of Human and Experimental Pathology, Pasteur Institute of Tunis, 13 Place Pasteur, BP74, 1002, Tunis, University of Tunis El Manar, Tunisia. Electronic address: samir.boubaker@pasteur.rns.tn.
authors.forename: Samir
authors.initials: S
authors.lastname: Boubaker
authors.affiliation: Laboratory of Venoms and Therapeutic Molecules, Pasteur Institute of Tunis, 13 Place Pasteur, BP74, 1002, Tunis, University of Tunis El Manar, Tunisia. Electronic address: Balkiss.Bouhaouala@pasteur.rns.tn.
authors.forename: Balkiss
authors.initials: B
authors.lastname: Bouhaouala-Zahar
authors.affiliation: Faculty of Pharmacy of Monastir, Rue Ibn Sina, 5000, University of Monastir, Tunisia. Electronic address: nadia.fenina@rns.tn.
authors.forename: Nadia
authors.initials: N
authors.lastname: Fenina
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D059451:Biosimilar Pharmaceuticals / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D017984:Enoxaparin / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007279:Injections, Subcutaneous; D008297:Male; D009929:Organ Size / Q000187:drug effects; D017208:Rats, Wistar; D018570:Risk Assessment; D013997:Time Factors; D018675:Toxicity Tests
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; D059451:Biosimilar Pharmaceuticals; D017984:Enoxaparin
keywords: Biosimilars; Enoxaparin; Preclinical; Repeated toxicity studies; Wistar rats