Orlando—Generic versions of low-molecular-weight heparin (LMWH) may not have the same efficacy and safety profile as branded products, according to investigators from Loyola University in Chicago, who presented their findings at the American Society of Hematology 2010 annual meeting (Abstract 1098).
Debra Hoppensteadt, PhD, compared several generic versions now in use outside the U.S. with enoxaparin and showed that while their molecular weight distributions were mostly similar, each of the products exhibited its own specific pharmacologic profile.
“This raises concerns about biosimilarity,” Dr. Hoppensteadt said in an interview at the meeting.
LMWHs are a heterogeneous group of polycomponent, polyfunctional and polytherapeutic agents. They are polydisperse and their pharmacologic effects are cumulative, representing the net effects of individual components. The effects of these agents are usually measured by indirect methods. The assays used for their potency evaluation only represent a single effect, such as the anti-Xa or anticoagulant effects. Sixty percent of the effects produced by these agents are non-anticoagulant and target other cells and processes that are not measured by routine methods, she explained.
“We did a side-by-side comparison, looking not just at clot-based parameters but going further, looking at such things as the release of tissue factor pathway inhibitor (TFPI) from the endothelial cells, which exerts an additional effect,” she said. “In other words, we took a more in-depth look at how these drugs work, examining important factors other than the traditional anticoagulant effect.”
The study compared branded enoxaparin (Lovenox) and three generic versions of enoxaparin---Cutenox, Versa and Fibrinox—in a primate model. Drugs were given at a dose of 1 mg/kg IV, which mirrors the dose used for acute coronary syndromes in humans, she said.
Several pharmacodynamic parameters were measured: TFPI release, thrombin activatable fibrinolytic inhibitor (TAFI) modulation and von Willebrand factor (vWF) release. In addition, by various assays the anticoagulant effects of these drugs were measured after IV administration. Simulated catheter-related thrombosis studies were also performed to differentiate each agent in contact, intrinsic and extrinsic clotting systems.
The analyses showed that the generic versions exhibited product-based pharmacodynamic differencess compared with the branded product. These are shown in the table:
The activated clotting time (ACT) values at 10 µg/ml varied from 172 to 200 seconds among the four products, Dr. Hoppensteadt reported. The ED50 values in the catheter-related thrombogenesis model varied considerably as well. Significant differences were also noted in the anticoagulant effects of the generic agents as compared with the branded product. Differences were also noted in HIT antibody-mediated aggregation studies. Heparin-induced thrombocytopenia (HIT) antibody-mediated aggregation of platelets varied from 17% to 28%.
“The pharmacodynamic differences between the branded and generic versions of LMWHs may be due to the higher dosages used and the potential IV administration, which leads to higher circulating levels of these agents,” she suggested. “Our observations suggest there is a need for additional animal studies and clinical trials to validate the use of generic versions of LMWHs.”