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

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.

Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary

“…Most are Phase I cross over studies in healthy volunteers, with subcutaneous single doses of 100, 400 and 600 mg enoxaparin or comparator. The general conclusions from these studies is that they are bioequivalent . One study has the focus on immunogenicity of a product from Brazil compared to the originator enoxaparin.…”

Innovative highlights of clinical drug trial design

“…11 Realistically for evaluating a generic version of the polysaccharide drug heparin, the activities of anti-factors Xa and IIa instead of pharmacokinetic parameters are used to be the official standard for human BE trials. 12 In consistent with the policy of FDA, European Medicines Agency has recently accepted the BE investigation in healthy human subjects for generic development of low molecular weight heparin without requiring RCTs in thromboembolism prone patients anymore. 13 Besides, utility of BE study is being expanded into the field of evaluating biosimilar products such as antibodies and fusion proteins which represent much larger and more complex molecules.…”

Use of Biomarkers in Pharmacokinetics Studies of Medicinal Products of Natural Origin

“…Этот подход активно использован в ряде работ, посвященных изучению фармакокинетики и/или биоэквивалентности гепаринсодержащих препаратов (на основе эноксапарина, далтепарина и др.) [2][3][4][5][6][7].…”