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Branded Versus Generic Enoxaparin: Biological Activity May Differ

TOP - August 2013 VOL 6, NO 3

While branded and generic enoxaparin share many traditional characteristics of low-molecular-weight heparins (LMWHs), they differ in several parameters that are relevant to an antithrombotic effect, according to researchers from Loyola University Medical Center, Maywood, Illinois, who presented their findings at the 54th Annual Meeting of the American Society of Hematology.

"While the traditional characteristics of average molecular weight, anti-FXa, and anti-FIIa potencies were not dissimilar for the generic and branded enoxaparins, other activities of this complex biological drug differed,” Jeanine Walenga, PhD, said.

LMWHs are anticoagulants whose heterogeneity in saccharide chain length and in the composition (sulfate, acetyl), content, and location of functional groups can impact their multiple biological activities. This study was conducted to compare the activity profile of the most widely used LMWH, branded enoxaparin (Lovenox), and the first United States–approved generic enoxaparin (Sandoz US).

Five batches each of branded and generic enoxaparin were studied in parallel. In addition to the anti-factor Xa (FXa) and anti-FIIa potencies, a battery of assays relevant to the antithrombotic activity of LMWHs was employed, covering molecular weight profiling, in vitro activities, and ex vivo pharmacodynamic responses. The concentration response of each batch of branded or generic drug was determined with blood from the same donor. Prefilled syringes containing 40 mg of enoxaparin were purchased through hospital pharmacies.

Similarities and Differences Observed

No significant differences were seen in the average molecular weight between branded and generic enoxaparins. However, both in vitro and in vivo/ex vivo activity differences were found in several parameters known to be relevant to the antithrombotic effect of LMWH, in particular, thrombin generation inhibition and tissue factor pathway inhibitor (TFPI) release, Walenga reported.

The investigations also demonstrated a wider variation in anticoagulant response to generic enoxaparin in comparison to branded enoxaparin. This variation was due to the response of the individual subject as well as to the batch of the product, she said. Differences appear to be more related to activities associated with the anti-FIIa (higher molecular weight) component of the LMWH.

The investigators summarized the main differences between branded and generic enoxaparin:

  • In vitro investigations
    • Anti-FXa and anti-FIIa potencies were similar; however, in the thromboelastography, fibrinokinetic, and thrombin generation inhibition assays, the generic compared with the branded enoxaparin showed:
      • More variation in the individual’s anticoagulant response
      • More batch-to-batch variation
      • Less predictable concentration-dependent and linear response
      • A lower overall anticoagulant effect
  • Ex vivo pharmacodynamic investigations
    • Generic compared with the branded enoxaparin demonstrated:
      • Less thrombin generation inhibition
      • Less TFPI release
      • More inhibition of the active form of thrombin-activatable fibrinolysis inhibitor

“These findings suggest that simple analytical characterization (average molecular weight, anti-FXa, anti-FIIa) can establish good quality control in manufacturing but may not assume similarity in biological performance between branded and generic enoxaparins,” Walenga said.

Besides the routinely required characterization, the inclusion of additional tests for biological activities and pharmacodynamic profiling of generics in animal models might provide useful information on the bioequivalence of the generic versions, the investigators suggested.

Walenga JM, Jeske W, Hoppensteadt D, et al. Comparative studies on branded enoxaparin and a US generic version of enoxaparin. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 2264.

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