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

PURPOSE: 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. PATIENTS AND METHODS: 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(max)) and area under the effect curve from time 0 to the last measured activity (T) (AUEC(0–T)) and AUEC from time 0 to infinity (AUEC(0–inf)) of anti-FXa activity, and A(max) and AUEC(0–T) of anti-FIIa activity. Secondary variables were A(max) and AUEC(0–T), AUEC(0–inf) of tissue factor pathway inhibitor, and the ratio of AUEC(0–T) 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%. RESULTS: 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(2). 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(max), AUEC(0–T) and AUEC(0–inf) for anti-FXa activity were 94.6%–105.9%, 99.8%–108.0% and 100.0%–108.6% respectively; A(max) and AUEC(0–T) 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. CONCLUSION: 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.