Bioequivalence of a biosimilar enoxaparin sodium to Clexane ® after single 100 mg subcutaneous dose: results of a randomized, double-blind, crossover study in healthy volunteers

• Published in: Drug design, development and therapy development and therapy, 2018-01, Vol.12, p.575-582
• Main Authors: Martínez González, Javier, Monreal, Mayte, Ayani Almagia, Ignacio, Llaudó Garín, Jordi, Ochoa Díaz de Monasterioguren, Lourdes, Gutierro Adúriz, Ibón
• Format: Article
• Language: English
• Subjects: anti-FIIa; anti-FXa; Anticoagulants; biosimilar; Body mass; Body mass index; Body size; Clinical medicine; Clinical trials; Double-blind studies; Drug dosages; Enoxaparin; Equivalence; FDA approval; Food; Heparin; Hepatitis; Informed consent; Inhibitors; Laboratories; LMWH; Males; Molecular weight; Original Research; Parameters; Pharmacodynamics; Pharmacokinetics; Pharmacology; Prescription drugs; Randomization; Sodium; TFPI; Tissue factor
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S162817

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.