The Immunogenic Potential of Generic Version of Low-Molecular-Weight Heparins May Not be the Same as the Branded Products

Abstract

translate into their safety and efficacy profiles in a given clinical indication. Therefore, the United States Food and Drug Administration (FDA) and other regulatory bodies consider each of the commercially available LMWHs as a distinct drug and require clinical validation for the approval of each of these in specific indications. The introduction of generic versions of the branded LMWHs has challenged the regulatory bodies to develop specific guidelines for their approval. The current guidelines for generic drug approval are not adequate because of the complex nature of the LMWHs due to biologic origins and chemical modifications of a polycomponent mixture of glycosaminoglycans. Although the incidence of HIT is rare with the use of LMWHs and heparinomimetics such as fondaparinux and idraparinux when used for prophylactic and therapeutic indications, these agents are capable of generating antibodies to heparin-PF4 complex, which are measurable by using immunologic methods. The relative prevalence of these antibodies is method-dependent owing to different capturing probes. Moreover, the relative proportion of antibody subtypes (immunoglobulin G, A, and M) differ from product to product. Up to 20% of the patients treated with LMWHs generate these antibodies. The pathophysiologic role of these antibodies remains unknown at this time. However, this immunogenic response is comparable to autoimmune responses observed in the case of the antiphospholipid syndrome. Additional data are needed to identify the role of these antibodies in various pathologic states and their impact on clinical outcomes. The FDA has been visionary in identifying the immunogenicity of LMWHs as an important criterion to differentiate and demonstrate the bioequivalence Heparin-induced thrombocytopenia (HIT) is a catastrophic adverse reaction associated with the use of heparins and related products. Although the incidence of HIT with low-molecularweight heparins (LMWHs) is much lower than with unfractionated heparin (UFH), these agents are capable of triggering immunogenic responses in 10% to 20% of the patients treated for different indications. The generation of these antibodies depends on the dosage, duration of treatment, patient population, and underlying comorbidities. Differences in the immunogenic responses among different branded LMWHs have been noted. These differences are due to the structural composition of the LMWH and the interactions with endogenous platelet factor 4 (PF4) and other proteins. Low-molecular-weight heparins have been differentiated on the basis of several biophysical, biochemical, and pharmacologic properties. These differences