• Martínez GonzálezJavierJR&D Department, Laboratorios Farmacéuticos Rovi S.A., Madrid, Spain., Mayte Monreal, Ignacio Ayani Almagia, Jordi Llaudó Garín, Lourdes Ochoa Díaz de Monasterioguren, and Ibón Gutierro Adúriz.
• R&D Department, Laboratorios Farmacéuticos Rovi S.A., Madrid, Spain.
• Drug Des Dev Ther. 2018 Jan 1; 12: 575-582.

PurposeTo 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 MethodsA 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 (Amax) and area under the effect curve from time 0 to the last measured activity (T) (AUEC0-T) and AUEC from time 0 to infinity (AUEC0-inf) of anti-FXa activity, and Amax and AUEC0-T of anti-FIIa activity. Secondary variables were Amax and AUEC0-T, AUEC0-inf of tissue factor pathway inhibitor, and the ratio of AUEC0-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%.ResultsThe 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/m2. 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 Amax, AUEC0-T and AUEC0-inf for anti-FXa activity were 94.6%-105.9%, 99.8%-108.0% and 100.0%-108.6% respectively; Amax and AUEC0-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.ConclusionThe 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.

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