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

Abstract

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 (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%.

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/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.

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.

Keywords: LMWH; TFPI; anti-FIIa; anti-FXa; biosimilar; pharmacodynamics; pharmacokinetics.

Conflict of interest statement

Disclosure All authors are employees of Laboratorios Farmacéuticos Rovi, S.A. The authors report no other conflicts of interest in this work.

Figures

Figure 1

Study flow chart and subject disposition.

Figure 2

Mean (SD) plasma anti-FXa (A) and anti-FIIa (B) activity, and baseline-adjusted TFPI levels (C) versus time curves (linear scale) after fasting of single doses of the test or reference drug. Notes: Test drug is enoxaparin sodium 100 mg (10,000 IU anti-FXa/1.0 mL) manufactured by Rovi, Madrid, Spain (●). Reference drug is enoxaparin sodium 100 mg (Clexane® 10,000 IU anti-FXa/1.0 mL) manufactured by Sanofi, Maison Alfort, France (■). Data shown from PK/PD analysis set (n=43). Abbreviations: PD, pharmacodynamic; PK, pharmacokinetic; SC, subcutaneous; TFPI, tissue factor pathway inhibitor.

Figure 3

Mean (SD) plasma anti-FXa (A) and anti-FIIa (B) activity, and baseline-adjusted TFPI levels (C) versus time curves (semi-logarithmic scale) after fasting SC administration of single doses of the test or reference drug. Notes: Test drug is enoxaparin sodium 100 mg (10,000 IU anti-FXa/1.0 mL) manufactured by Rovi, Madrid, Spain (●). Reference drug is enoxaparin sodium 100 mg (Clexane® 10,000 IU anti-FXa/1.0 mL) manufactured by Sanofi, Maison Alfort, France (■). Data shown from PK/PD analysis set (n=43). Abbreviations: PD, pharmacodynamic; PK, pharmacokinetic; SC, subcutaneous; TFPI, tissue factor pathway inhibitor.